2-quaternary heteroarylalkylthio carbapenems having an acid moiety substituent

ABSTRACT

Compounds of the formula: ##STR1## wherein ##STR2## is a quaternized, monocyclic or bicyclic heteroaryl group, substituted by an acid moiety, and their preparation and use as antibiotics are disclosed.

REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. Nos. 744,740 and 744,741, both filed June 17, 1985, both nowabandoned; and of Ser. No. 123,494, filed Nov. 20, 1987.

BACKGROUND OF THE INVENTION

The present invention is concerned with improved carbapenem antibioticscharacterized by having a monocyclic or bicyclic quaternaryheteroarylalkylthio substituent in the 2-position. The heteroarylportion of the substituent is further substituted with an acidic moiety.

Thienamycin is a known carbapenem, broad spectrum antibiotic of theformula: ##STR3## Other derivatives of A are also known. The presentquaternary, monocyclic or bicyclic heteroarylalkylthio substitutedcarbapenems have an antibiotic spectrum similar to or better than A. Thepresent carbapenems also exhibit reduced seizure potential, i.e., lesstendency to produce convulsions, when compared to the N-formimidoyl andN-acetimidoyl derivatives of A, and to related quaternary, monocyclic orbicyclic heteroarylalkylthio substituted carbapenems that lack theadditional acidic moiety in the heteroaryl group.

U.S. Pat. No. 4,552,696 (Kim and Misco) discloses carbapenem antibioticshaving a 2-sidechain of the formula ##STR4## wherein a possiblesubstituent of the heteroaryl group is carboxyl. However, this carboxylsubstituent is only one of a vast number of other enumeratedsubstituents, and no special significance of any kind is attached to it.Furthermore, the patent disclosure contains data relating to "ToxicityAfter Intracranial Administration to Mice" and thus demonstrates anawareness of the problem of convulsive potential. Yet, there is noappreciation that an acidic moiety in the heteroaryl group, which makesthe carbapenem compound overall an anionic zwitterion, will uniformlyconfer a significantly reduced tendency to produce convulsions in theoverall compound.

SUMMARY OF THE INVENTION

The present invention provides novel carbapenem compounds of theformula: ##STR5## wherein R is H or CH₃ ; R¹ and R² are independently H,CH₃ --, CH₃ CH₂ --, (CH₃)₂ CH--, HOCH₂ --, CH₃ CH(OH)--, (CH₃)₂ C(OH)--,FCH₂ --, F₂ CH--, F₃ C--, CH₃ CH(F)--, CH₃ CF₂ --, or (CH₃)₂ C(F)--;##STR6## is a quaternary, monocyclic or bicyclic, substituted heteroarylgroup containing (a) when monocyclic, up to 4 heteroatoms and up to 6total ring atoms or (b) when bicyclic up to 6 heteroatoms and 9-10 ringatoms. The heteroaryl group is required to be substituted by an acidicsidechain of the structure --B or --(CH₂)_(n) --X--(CH₂)_(m) --W--Bwhere:

n is 0-4;

m is 0-4,;

x is CR^(s) R^(t) ; CH═CH; phenylene (--C₆ H₄ --); NH; N(C₁ -C₄ alkyl);O; S; S═O; C═O; SO₂ ; SO₂ NH; CO₂ ; CONH; OCO₂ ; OC═O; or NHC═O; whereR^(t) is H or C₁ -C₄ -alkyl; and R^(s) is H, OH, C₁ -C₄ -alkyl, O(C₁ -C₄alkyl), NH₂, NH(C₁ -C₄ alkyl), N(C₁ -C₄ alkyl)₂, CN, CONH₂, CON(C₁ -C₄alkyl)₂, CO₂ H, SO₂ NH₂, or SO₂ NH(C₁ -C₄ alkyl);

W is a single bond; NH; N(C₁ -C₄ alkyl); O; or S;

B is an acidic function selected from carboxy (CO₂ H); phosphono[P═O(OH)₂ ]; alkylphosphono {P═O(OH)--[O(C₁ -C₄ alkyl)]};alkylphosphinyl [P═O(OH)--(C₁ -C₄ alkyl)]; phosphoramido [P═O(OH)NH₂ ];substituted phosphoramido [P═O(OH)NH(C₁ -C₄ alkyl) and P═O(OH)NHR^(x) ];sulfino (SO₂ H); sulfo(SO₃ H); 5-tetrazolyl (CN₄ H); arylsulfonamido(SO₂ NHR^(x)); CONHR^(v) ; SO₂ NHR^(v) and acylsulfonamido selected fromthe structures CONHSO₂ R^(x), CONHSO₂ NH₂, CONHSO₂ (C₁ -C₄ alkyl),CONHSO₂ NH(C₁ -C₄ alkyl), CONHSO₂ N(C₁ -C₄ alkyl)₂, SO₂ NHCO(C₁ -C₄alkyl), SO₂ NHCONH₂, SO₂ NHCONH(C₁ -C₄ -alkyl), SO₂ NHCON(C₁ -C₄alkyl)₂, SO₂ NHCOR^(x), SO₂ NHCN, SO₂ NHCSNH₂, SO₂ NHCSNH (C₁ -C₄alkyl), SO₂ NHCSN(C₁ -C₄ alkyl)₂, SO₂ NHSO₂ R^(x), and SO₂ NHSO₂ R^(w),where R^(x) is substituted or unsubstituted phenyl, naphthyl, orheteroaryl; R^(w) is C₁ -C₄ alkyl, NH₂, NH(C₁ -C₄ alkyl), N(C₁ -C₄alkyl)₂, OH, or O(C₁ -C₄ alkyl); and R^(v) is OH, SH, O(C₁ -C₆ alkyl),S(C₁ -C₆ alkyl), O-phenyl, S-Phenyl, O-heteroaryl, S-heteroaryl; wherefor R^(x) and R^(v) heteroaryl means (a) a monocyclic group having 5 or6 total ring atoms in which from 1 to 4 carbon ring atoms are replacedby heteroatoms selected from N, O, and S, or (b) a bicyclic group having9 or 10 total ring atoms in which from 1 to 6 carbon ring atoms arereplaced by heteroatoms selected from N, O, and S; and where for R^(x)and R^(v) the phenyl, naphthyl, and heteroaryl groups may be furthermono- or disubstituted by groups independently selected from C₁ -C₄alkyl; C₁ -C₄ -alkoxy; Br; Cl; F; CF₃ ; OH; (C₁ -C₄ alkyl)carbonyloxy;carbamoyl, carbamoyloxy, sulfamoyl, and amino where the nitrogen may beunsubstituted or mono- or disubstituted with C₁ -C₄ alkyl; C₁ -C₄alkylthio; C₁ -C₄ alkylsulfinyl; C₁ -C₄ alkylsulfonyl; formylamino; (C₁-C₄ alkyl)carbonylamino; (C₁ -C₄ alkoxyl)-carbonylamino; ureido in whichthe terminal nitrogen may be unsubstituted or substituted by C₁ -C₄alkyl; (C₁ -C₄ alkyl)sulfonamido; cyano; (C₁ -C₄ alkoxyl)carbonyl;thiocarbamoyl; nitro; carboxyl; formyl; and (C₁ -C₄ alkyl)carbonyl.

In addition, the heteroaryl group ##STR7## is optionally substituted byone to three of the radicals independently selected from the groupconsisting of:

(a) a trifluoromethyl group: --CF₃ ;

(b) a halogen atom: --Br, --Cl, --F, or --I;

(c) C₁ -C₄ alkoxy radical: --OC₁₋₄ alkyl;

(d) a hydroxy group: --OH;

(e) (C₁ -C₆ alkyl) carbonyloxy radical: ##STR8## (f) a carbamoyloxyradical which is unsubstituted or substituted on nitrogen with one ortwo C₁ -C₄ alkyl groups: ##STR9## where R^(y) and R^(z) areindependently H or C₁₋₄ alkyl; (g) a C₁ -C₆ alkylthio radical, C₁ -C₆alkylsulfinyl radical or C₁ -C₆ alkylsulfonyl radical: ##STR10## alkylwhere n=0-2; (h) a sulfamoyl group which is unsubstituted or substitutedon nitrogen by one or two C₁ -C₄ alkyl groups: ##STR11## where R^(y) andR^(z) are as defined above; (i) an amino group, or a mono (C₁ -C₄ alkyl)amino or di(C₁ -C₄ alkyl)-amino group: ##STR12## where R^(y) and R^(z)are as defined above; (j) a formylamino group: ##STR13## (k) substitutedor unsubstituted (C₁ -C₆ alkyl)carbonylamino radical: ##STR14## (l) a(C₁ -C₄ alkoxy) carbonylamino radical: ##STR15## (m) a ureido group inwhich the terminal nitrogen is unsubstituted or substituted with one ortwo C₁ -C₄ alkyl group: ##STR16## where R^(y) and R^(z) are as definedabove; (n) a C₁ -C₆ alkyl sulfonamido group: ##STR17## (o) a cyanogroup: --CN; (p) a formyl or acetalized formyl radical: ##STR18## (g)(C₁ -C₆ alkyl)carbonyl radical: ##STR19## (r) substituted orunsubstituted phenylcarbonyl or heteroarylcarbonyl: ##STR20## (s) ahydroximinomethyl radical in which the oxygen or carbon atom isoptionally substituted by a C₁ -C₄ alkyl group: ##STR21## where R^(y)and R^(z) are as defined above; (t) a (C₁ -C₆ alkoxy)carbonyl radical:##STR22## (u) a carbamoyl radical which is unsubstituted or substitutedon nitrogen by one or two C₁ -C₄ alkyl groups: ##STR23## where R^(y) andR^(z) are as defined above; (v) an N-hydroxycarbamoyl or N(C₁ -C₄alkoxy)carbamoyl radical in which the nitrogen atom may be additionallysubstituted by a C₁ -C₄ alkyl group: ##STR24## where R^(y) and R^(z) areas defined above; (w) a thiocarbamoyl group: ##STR25## (x) an amidinogroup ##STR26## where R⁵, R⁶ and R⁷ are independently hydrogen, C₁ -C₄alkyl or wherein two of the alkyl groups together form a C₂ -C₆ alkyleneradical optionally interrupted by a heteroatom and joined together toform a ring;

(y) a guanidinyl group where R⁵ in (x) above is NR⁸ R⁹ and R⁸ and R⁹ areas defined for R⁵ through R⁷ above;

(z) a carbamimidoyl group ##STR27## where R⁵, R⁶ and R⁷ are as definedabove; (aa) a C₂ -C₆ alkenyl radical;

(ab) a C₂ -C₆ alkynyl radical;

(ac) a C₃ -C₇ cycloalkyl radical;

(ad) a C₅ -C₇ cycloalkenyl radical;

(ae) a substituted or unsubstituted phenyl or heteroaryl group;

(af) a sulfo group: --SO₃ H;

(ag) a carboxy group: --COOH;

(ah) C₁ -C₆ alkyl radical; and

(ai) C₁ -C₄ alkyl monosubstituted by one of the substituents (a)-(ag)above;

wherein for those radicals above which are indicated to be optionallysubstituted, the substituents are one or two in number and independentlyselected from hydroxy, C₁ -C₄ alkoxy, mercapto, amino, mono- or di(C₁-C₄ alkyl)amino, cyano, halo, CF₃, COOH, sulfo, carbamoyl, andsulfamoyl;

L is a substituted or unsubstituted, straight or branched chain,bivalent C₁ -C₆ alkyl, C₂ -C₆ alkenyl or C₃ -C₆ cycloalkyl, or C₁ -C₄alkyl-X--C₁ -C₄ alkyl wherein X is O, S, NH, or N(C₁₋₄ alkyl), whereinthe substituents are selected from radicals (a) through (ai) definedabove; ##STR28## together, in addition to the individual definitions ofL and ##STR29## above, may be the group ##STR30## where ##STR31## is a5- to 6-membered heteroaryl group containing from one to threeheteroatoms which is substituted by an acidic moiety, and which isoptionally substituted by one or more members independently selectedfrom the group consisting of the substituents defined as (a)-(ai) under##STR32## and A and D are independently selected from a direct bond or asubstituted or unsubstituted C₁ -C₄ alkylene group optionallyinterrupted by a heteroatom; provided that, A and D cannot both be adirect bond, and that the ring containing A and D contains from 5 to 8atoms; and wherein the substituents on A and D are selected fromhydroxyl, C₁ -C₃ alkoxy, amino, carboxyl, cyano, carbamoyl,trifluoromethyl, C₁ -C₄ alkyl, and di(C₁ -C₄ alkyl)amino; and

Y is selected from:

(i) COOH or a pharmaceutically acceptable ester or salt thereof,

(ii) COOR³ wherein R³ is a readily removable carboxyl covering group,

(iii) COOM wherein M is an alkali metal, or

(iv) COO⊖, provided that an additional compensating cationic group ispresent in the structure.

The most common Y group of the present invention is COOM wherein M is ametal cation such as Na, K, or 1/2 Ca. Since the heteroarylium group issubstituted by an acidic substituent which is predominantly ionized,that is anionic, at or near neutral PH in aqueous solution, the Y groupis usually of the salt form COOM. In structural terms wherein B⊖represents the ionized or anionic form of the acidic group, thecompounds of the present invention can be represented as shown belowwherein all charges are compensated for. ##STR33## It should be notedthat it is possible for the M group to be located at either the carboxylor B center as long as the net charge of the compound remains zero.Compounds of this type are referred to as anionic zwitterions since thatis the overall charge type of the molecule when excluding the external Mcation. If the compound where additionally substituted by a cationicgroup such as an ammonium substituent, the compensatory, M group wouldnot be required and the compound would be a double zwitterion.

The substituent R=methyl may be of either configuration, i.e., the α orβ-stereoisomer. The β- stereoisomer is preferred, since it has beenfound that this configuration gives improved stability toward the DHP-Ienzyme.

The ##STR34## group must have an acidic sidechain but m optionally havefrom 1 to 3 additional substituents which may be the same or differentand are selected on an independent basis. While a single such additionalsubstituent is usually preferred, there is occasion to use up to threesuch substituents, e.g., where it is desired to enhance the effect of aparticular substituent group by employing multiple substituents. Thus,two sulfomethyl substituents may be used. At other times it may bedesired to employ a substituent known to enhance antibacterial activityof the overall molecule against a particular bacterium, for example,while also employing a substituent known to improve the duration ofaction of the overall molecule.

With reference to the above definitions, "alkyl" means a straight orbranched chain aliphatic hydrocarbon radical.

The term "heteroatom" means N, S, or O, selected on an independentbasis.

Under the definition of "Y", the term "pharmaceutically acceptable esteror salt" refers to those salt and ester forms of the compounds of thepresent invention which would be apparent to the pharmaceutical chemist,i.e., those which are non-toxic and which would favorably affect thepharmacokinetic properties of said compounds, their palatability,absorption, distribution, metabolism and excretion. Other factors, morepractical in nature, which are also important in the selection, are costof raw materials, ease of crystallization, yield, stability,hygroscopicity, and flowability of the resulting bulk drug. Since thecompounds of the present invention may be carboxylates, the salts wouldbe cations such as benzathine, chloroprocaine, choline, diethanolamine,meglumine and procaine. The metallic cations such as aluminum, calcium,lithium, magnesium and zinc are potential choices. The alkali metalcations sodium and potassium are specifically defined.

The term "readily removable carboxyl covering group" means aconventional substituent which takes the place of the acidic hydrogen ofthe carboxyl group and thereby prevents said group from reacting withany of the reagents employed in the various steps of the overallsynthesis. Such covering of the carboxyl group is often necessary toprevent unwanted competing reactions involving said carboxyl group fromtaking place. Thus, all of these compounds are intermediates. Theconventional covering substituent must also be "readily removable", bywhich is meant that it is selectively removable, i.e., it is not likelyto be removed during the course of ordinary procedures which are to becarried out on the carbapenem nucleus and sidechains, while, on theother hand, it is likely to be removed by procedures which are not soharsh as to disturb the basic ring structure of the carbapenem nucleusor unprotected substituents thereon.

It is preferred that when one of R¹ or R² is H, the other is (R)CH₃CH(OH)-- or (R)CH₃ CH(F)--; and (R)CH₃ CH(OH)-- is most preferred.

A preferred group of compounds of Formula I are those where L is C₁ -C₆branched or linear alkyl, both substituted and unsubstituted. Thepreferred substituents are OH, CF₃, OC₁₋₄ alkyl, CN, CONH₂, CONH(C₁ -C₄alkyl), CON(C₁ -C₄ alkyl)₂, COOH, NH₂, NH(C₁ -C₄ alkyl), and N(C₁ -C₄alkyl)₂ and especially OCH₃, OH, NH₂, and CF₃. Examples of preferred Lgroups are --CH₂ --, --CH(CH₃)--, --CH(CH₂ CH₃)--, --CH(CH₂ OCH₃), --CH₂--CH₂ --, --CH(CH₃)--CH₂ --, --CH(CH₂ CH₃)--CH₂ --, --C(CH₃)₂ --CH₂ --,--(CH₂)₃ --, --CH(CH₃)--(CH₂)₂ --, CH₂ --CH(CH₃)--, --CH₂ --C(CH₃)₂--CH₂ --, --(CH₂)₄ --, --CH(CF₃)--CH₂ --, --CH(CH₂ OH)--CH₂ --, --CH(CH₂NH₂)--CH₂ --, --CH(CH₂ OCH₃)--CH₂ --, and the like.

Especially preferred compounds of Formula I compounds are those where Lis --CH₂ --, --CH₂ CH₂ -- or --CH(CH₃)CH₂ --. Of course it is understoodthat where any substituent group has an asymmetric center e.g. ##STR35##then all stereoisomers are included as mixtures or as separate isomers.

In the preferred embodiment, the ##STR36## group is quaternized,monocyclic heteroaryl, substituted by an acidic group and optionallysubstituted by one or more additional substituents, containing inaddition to the quaternary N, up to 2 additional hetero atoms selectedfrom O, N and S.

Representative useful monocyclic ##STR37## groups are substitutedpyridinium, pyridazinium, pyrimidinium, pyrazinium, pyrazolium,triazolium, imidiazolium, thiazolium, oxazolium, isoxazolium and thelike.

The pyridinium group is most preferred since it provides, whenincorporated into the carbapenem final product, the desired propertiesof good antibacterial spectrum and potency combined with chemicalstability. It also provides ready availability and ease of handling as astarting material. However, any of the other groups set out above, aswell as those falling within the definition of ##STR38## set out hereinbut not specifically described above, are also suitable, althoughperhaps in some cases less desirable in terms of one or more of thecriteria mentioned above.

Preferred Formula I compounds are those where monocyclic ##STR39## is asix membered heteroaryl, such as substituted pyridinium, pyridazinium orpyrazinium, and preferably substituted pyridinium, wherein the acidicmoiety is selected from COOH, (C₁ -C₄ alkyl)COOH, SO₃ H, (C₁ -C₄ alkyl)SO₃ H, SO₂ NH(heteroaryl), (C₁ -C₄ alkyl) SO₂ NH (heteroaryl), and (C₁C₄ alkyl) SO₂ NHCN; and the optional substituents (one to three) areselected from OH, NH₂, NHCH₃, OCH₃, COO--C₁ -C₃ alkyl, C(O)NHOH,phenyl,N(CH₃)₂, C(O)CH₃, C(O)N(CH₃)OH, SO₃ H, SCH₃, CHO, COOH, S(O)CH₃,SO₂ CH₃, SO₂ NH₂, SO₂ NHCH₃, SO₂ CH₃, CN, CSNH₂, Cl, F, Br, CF₃, CONH₂,CONH(CH₃), CH═N--OH, C₁ -C₆ alkenyl and substituted and unsubstituted C₁-C₆ alkyl.

The most preferred acidic moieties are SO₃ H, CH₂ SO₃, CH₂ CH₂ SO₂NH(heteroaryl), and CH₂ SO₂ NHCN; and the most preferred optionalsubstituents are C₁ -C₆ alkyl, NH₂, NHCH₃, OCH₃, Cl, F, Br, CF₃,N(CH₃)₂, SCH₃, S(O)CH₃, SO₂ CH₃, SO₂ NH₂, SO₂ NHCH₃, CN, CSNH₂,CH═N--OH, CONH₂, CONH(CH₃).

The compounds of the present invention are characterized by having anacidic substituent on the N-containing mono- or bicyclic quaternaryheteroaryl group in the 2-position. The acidic substituent forms ananion under physiologic conditions of pH, and this anionic site,combined with the quaternary nitrogen center and the carboxylate group,lead to compounds that are overall anionic zwitterions. This novelcharacteristic has been found to result in at least one surprising andimportant improvement in the biological properties of the compounds,reduced CNS side-effects. A more particular group of the compounds,those wherein the acidic function is a sulfoalky group of the formulaCH₂ SO₃ H, CH₂ SO₂ NH (heteroaryl), or CH₂ SO₂ NHCN, have been found tohave the additional surprising and important biological property ofenhanced potency against Pseudomonas species, an especially importantnosocomial pathogen. In this most preferred group of compounds, it ispreferred that the N-containing mono- or bicyclic quaternary heteroarylgroup in the 2-position is pyridinium, the linking moiety L is --CH₂ CH₂--, and the acidic substituent is CH₂ SO₃ H, CH₂ SO₂ NH(heteroaryl), orCH₂ SO₂ NHCN.

An especially preferred subgenus of compounds within the scope of thepresent invention are 2-[4-(N-cyanosulfamoylmethyl)-1-pyridinium]ethylthio carbapenems of the following formula: ##STR40## where R is Hor CH₃ ;

R' is H, F, Cl, NH₂, CH₃, SO₂ NHCH₃, SO₂ NH₂, SO₂ CH₃, OCH₃, CONH₂,S(O)CH₃, or CONHCH₃ ; and

Y is as defined above.

Within this subgenus, the preferred compounds are those wherein R is Hand R' is H, F, or Cl.

Representative examples of preferred ##STR41## pyridinium groups andsubstituents are those having the following formulas: ##STR42##Especially preferred compounds are those of structure to wherein R is Hor CH₃ and the heteroarylium moiety ##STR43## is selected from thegroups shown below: ##STR44##

Representative examples of preferred monocyclic ##STR45## other thanpyridinium, with preferred substituents, are those having the followingformulas: ##STR46##

In another preferred embodiment, the ##STR47## group is a quaternized,bicylic, heteroaryl substituted by an acidic group, and containing inaddition to the quaternary N, up to 5 additional heteroatomsindependently selected from O, N and S, and 9-10 total ring atoms.

Representative useful ##STR48## groups are substituted and unsubstitutedquinolinium,, isoquinolinium, quinoxalinium, isocinolinium,thienopyridinium, furopyridinium, naphthyridinium, pyrazinopyridinium##STR49## where D is C₂₋₆ alkylene ring which may be interrupted by oneor more O, S or N heteroatoms.

Preferred Formula I compounds are those where ##STR50## is a bicyclic 9or 10 membered ring, and more preferably substituted quinolinium,isoquinolinium, or thienopyridinium.

In addition to the acidic group, which may be on either of the rings ofthe bicyclic heteroaryl, optionally one to three additional substituentsmay be present. The preferred additional substituents, as well as thepreferred acidic groups, are the same as those for the monocylicheteroaryl groups, which have been described further above.

Representative examples of preferred bicyclic ##STR51## with preferredsubstituents, are those having the following formulas: ##STR52##

Where ##STR53## representative examples of preferred groups are:##STR54## wherein R¹ is H or a suitable acidic substituent such as CO₂H, SO₃ H, or C₁ -C₄ alkyl substituted by CO₂ H or SO₃ H and R² issubstituted or unsubstituted C₁ -C₄ alkyl wherein the substituents areselected from OH, N(C₁ -C₃ alkyl)₂, CN, CONH₂, and O(C₁ -C₄ alkyl).Alternatively, R² can be a suitable acidic group such as C₁ -C₄ alkylsubstituted by CO₂ H or SO₃ H and R¹ is one of the optional substituentsmentioned below.

The heteroarylium group may be optionally substituted by a groupselected from C₁ -C₃ alkyl, CN, CONH₂, NH₂, NH(C₁ -C₃ alkyl), N(C₁ -C₃aIkyl)₂, OH, O(C₁ -C₄ alkyl), SO₂ NH₂, CH₂ N(C₁ -C₃ alkyl)₂, Br, F, SO₂NH₂, and SO₂ NH(C₁₋₃ alkyl).

Especially preferred ##STR55## groups are where (a) A is (CH₂)₂ or(CH₂)₃, and D is a single bond, (b) A is CH₂ and D is CH₂ or (CH₂)₂, or(c) A is a single bond and D is (CH₂)₂₋₃, and the heteroaryl moiety ispreferably pyridinium, thiazolium, or imidiazolium.

The compounds of Formula I include anionic zwitterion salts when Y isCOOM: ##STR56## or, when Y is other than COOM, inner (zwitterionic)salts: ##STR57## R°.spsp.a is a pharmaceutically acceptable ester, e.g.,pivaloyloxymethyl, phthalidyl, phthalimidomethyl, acetoxmethyl,ethoxycarbonyloxyethyl, pivaloyloxyethyl,4-methyl-2-oxo-1,3-dioxolen-5-yl-methyl.

Again, the compounds of Formula I include the stereoisomers as mixturesand as separate isomers.

Compounds having the (5R,6S,8R) or (1R, 5S, 6S, 8R) stereochemistryshown below are preferred: ##STR58## or when L contains a chiral center,the side chain chirality leads to diastereomeric products. The productscan be separated by conventional methods, used as mixtures orsynthesized stereospecifically from optically active mercaptans.Representative zwitterionic structures are shown below: ##STR59##

For many of the compounds exemplified in this specification, the Rsubstituent is hydrogen. This is the result of a more facile synthesisfor such compounds, however, and does not evidence any reference forR=hydrogen. To the contrary, the compounds wherein R=methyl will oftenbe found to possess greater stability to dehydropeptidase (DHP-I)enzyme, a renal dipeptidase which mediates lactam hydrolysis ofcarbapenem compounds in man, resulting in significantly reduced urinaryrecoveries.

The carbapenem compounds of the present invention are useful per se andin their pharmaceutically acceptable salt and ester forms in thetreatment of bacterial infections in animal and human subjects.Conveniently, pharmaceutical compositions may be prepared from theactive ingredients in combination with pharmaceutically acceptablecarriers. Thus, the present invention is also concerned withpharmaceutical compositions and methods of treating bacterial infectionsutilizing as an active ingredient the novel carbapenem compounds of thepresent invention.

The pharmaceutically acceptable salts referred to above includenon-toxic acid addition salts. The Formula I compounds be used in theform of salts derived from inorganic or organic acids. Included amongsuch salts are the following: acetate, adipate, alginate, aspartate,benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate,camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate.Also, the basic nitrogen-containing groups can be quaternized with suchagents as lower alkyl halides, such as methyl, ethyl, propyl, and butylchloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl,dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl,myristyl and stearyl chlorides, bromides and iodides, aralkyl halideslike benzyl and phenethyl bromides and others. Water or oil-soluble ordispersible products are thereby obtained.

The pharmaceutically acceptable esters of the novel carbapenem compoundsof the present invention are such as would be readily apparent to amedicinal chemist, and include, for example, those described in detailin U.S. Pat. No. 4,309,438, Column 9, line 61 to Column 12, line 51,which is incorporated herein by reference. Included within suchpharmaceutically acceptable esters are those which are hydrolyzed underphysiological conditions, such as pivaloyloxymethyl, acetoxymethyl,phthalidyl, indanyl and methoxymethyl, and those described in detail inU.S. Pat. No. 4,479,947, which is incorporated herein by reference.

The novel carbapenem compounds of the present invention may also takethe form where Y is COOR³, where R³ is a readily removable carboxylcovering group. Such conventional covering groups consist of known estergroups which are used to protectively cover the carboxyl group duringthe synthesis procedures described further below. These conventionalcovering groups are readily removable, i.e., they can be removed, ifdesired, by procedures which will not cause cleavage or other disruptionof the remaining portions of the molecule. Such procedures includechemical and enzymatic hydrolysis, treatment with chemical reducingagents under mild conditions, and catalytic hydrogenation. Examples ofsuch ester protecting groups include benzhydryl, p-nitrobenzyl,2-naphthylmethyl, allyl, benzyl, trichloroethyl, silyl such astrimethylsilyl, phenacyl, p-methoxybenzyl, acetonyl, o-nitrobenzyl,4-pyridylmethyl, and C₁ -C₆ alkyl such as methyl, ethyl or t-butyl.

The compounds of the present invention are valuable antibacterial agentsactive against various Gram-positive and Gram-negative bacteria andaccordingly find utility in human and veterinary medicine.Representative pathogens which are sensitive to the antibacterial agentsof the present invention include various species of the following:Staphylococcus, Enterococcus, Escherichia Coli, Klebsiella,Enterobacter, Bacillus, Salmonella, Pseudomonas, Serratia and Proteus.The antibacterials of the invention are not limited to utility asmedicaments; they may be used in all manner of industry, for example:additives to animal feed, preservation of food, disinfectants, and inother industrial systems where control of bacterial growth is desired.For example, they may be employed in aqueous compositions inconcentrations ranging from 0.1 to 100 parts of antibiotic per millionparts of solution in order to destroy or inhibit the growth of harmfulbacteria on medical and dental equipment and as bactericides inindustrial applications, for example in waterbased paints and in thewhite water of paper mills to inhibit the growth of harmful bacteria.

The compounds of this invention may be used in any of a variety ofpharmaceutical preparations. They may be employed in capsule, powderform, in liquid solution, or in suspension. They may be administered bya variety of means; those of principal interest include: typically orparenterally by injection (intravenously or intramuscularly).

Compositions for injection, a preferred route of delivery, may beprepared in unit dosage form in ampules, or in multidose containers. Thecompositions may take such forms as suspensions, solutions, or emulsionsin oily or aqueous vehicles, and may contain formulatory agents.Alternatively, the active ingredient may be in powder form forreconstitution, at the time of delivery, with a suitable vehicle, suchas sterile water. Topical applications may be formulated in hydrophobicor hydrophilic bases as ointments, creams, lotions, paints, or powders.

The dosage to be administered depends to a large extent upon thecondition and size of the subject being treated as well as the route andfrequency of administration--the parenteral route by injection beingpreferred for generalized infections. Such matters, however, are left tothe routine discretion of the therapist according to principles oftreatment well known in the antibacterial art. In general, a dailydosage consists of from about 5 to about 600 mg of active ingredient perkg of body weight of the subject in one or more treatments per day. Apreferred daily dosage for adult humans lies in the range of from about10 to 240 mg of active ingredient per kg of body weight. Another factorinfluencing the precise dosage regimen, apart from the nature of theinfection and peculiar identity of the individual being treated, is themolecular weight of the chosen species of this invention.

The compositions for human delivery per unit dosage, whether liquid orsolid, may contain from 0.1% to 99% of active material, the preferredrange being from about 10-60%. The composition will generally containfrom about 15 mg to about 1500 mg of the active ingredient; however, ingeneral, it is preferable to employ a dosage amount in the range of fromabout 250 mg to 1000 mg. In parenteral administration, the unit dosageis usually the pure compound I in sterile water solution or in the formof a soluble powder intended for solution.

The preferred method of administration of the Formula I antibacterialcompounds is parenteral by i.v. infusion, i.v. bolus, or i.m. injection.

For adults, 5-50 mg of Formula I antibacterial compounds per kg of bodyweight given 2, 3, or 4 times per day is preferred. Preferred dosage is250 mg to 1000 mg of the Formula I antibacterial given two (b.i.d.)three (t.i.d.) or four (q.i.d.) times per day. More specifically, formild infections, and particularly urinary tract infections, a dose of250 mg t.i.d. or q.i.d. is recommended. For moderate infections againsthighly susceptible gram positive and gram negative organisms, a dose of500 mg t.i.d. or q.i.d. is recommended. For severe, life-threateninginfections against organisms at the upper limits of sensitivity to theantibiotic, a dose of 1000 mg t.i.d. or q.i.d. is recommended.

For children, a dose of 5-25 mg/kg of body weight given 2, 3, or 4 timesper day is preferred; a dose of 10 mg/kg t.i.d. or q.i.d. is usuallyrecommended.

Antibacterial compounds of Formula I are of the broad class known ascarbapenems or 1-carbadethiapenems. Certain of these carbapenems aresusceptible to attack by a renal enzyme known as dehydropeptidase (DHP).This attack or degradation may reduce the efficacy of the carbapenemantibacterial agent. Inhibitors of DHP and their use with carbapenemantibacterial agents are disclosed in the prior art [see European PatentApplications No. 79102616.4 filed July 24, 1979 (Patent No. 0 010 573);79102615.6, filed July 24, 1979 (Patent No. 0 007 614); and No.82107174.3, filed Aug. 9, 1982 (Publication No. 0 072 014)].

The compounds of the present invention may, where DHP inhibition isdesired or necessary, be combined or used with the appropriate DHPinhibitor as described in the aforesaid patents and publishedapplication. Thus, to the extent that the cited European patentapplications 1.define the procedure for determining DHP susceptibilityof the present carbapenems and 2.disclose suitable inhibitors,combination compositions and methods of treatment, they are incorporatedherein by reference. A preferred weight ratio of Formula I compound:DHPinhibitor in the combination compositions is about 1:1. A preferred DHPinhibitor is7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptenoicacid or a useful salt thereof.

These combination compositions and their use are further embodiments ofthe present invention.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of Formula I may be prepared by any convenient process.

One such process is illustrated of the following reaction equations:##STR60## where R° is other than (-) or H and is a readily removablecarboxyl covering group e.g. p-NO₂ benzyl or allyl. x is a leaving groupsuch as OP(O)(O0)₂, ##STR61## OSO₂ CF₃, S(O)R" where R" is CH₃, CH₂ CH₃,CH₂ CH₂ NHC(O)CH₃ and the like.

The process conditions are generally those available in the prior art.Thus, the side chain addition reaction is carried out in a solvent suchas acetonitrile, dimethylformamide, dimethylacetamide, tetrahydrofuran,or N-ethylpyrrolidinone with or without added water to solubilize thereactants in the presence of a base such as N,N-diisopropylethylamine,triethylamine, or 4-dimethylaminopryidine at a temperature of from -40°C. to 25° C. for a period of 5 minutes to 10 hours. The deblockingreaction wherein R° is p-nitrobenzyl is usually conducted in an aqueoussystem containing cosolvents such as tetrahydrofuran, ethanol,n-butanol, 2-amyl alcohol, of ethyl acetate and a pH 6.8-7.0 aqueousbuffer. Suitable buffers include phosphate buffers and buffers derivedfrom non-nucleophilic amines such as N-methylmorpholine ormorpholinopropane sulfonic acid. The reaction is conducted at 0° C. to40° C. for 0.5 to 5 hours under 1-100 atmospheres of hydrogen in thepresence of a catalyst such as 10% palladium on carbon or 20% palladiumhydroxide on carbon. The final products are purified by ion exchangechromatography and/or reverse phase chromatography, exclusionchromatography, or by a combination of these techniques. When apharmaceutically acceptable ester of the final product is desired, thedeblocking step is omitted and the appropriate R° group is incorporatedinto the starting material.

A second process for preparing Formula I compounds is illustrated by thefollowing reaction equations: ##STR62##

Again, the process conditions are those available in the prior art.

A third process for preparing Formula I compounds is illustrated by thefollowing equations: ##STR63##

Again, the process conditions are those available in the prior art.

Following are examples illustrating the preparation of compounds ofFormula I. Examples 1-10, 65 and 66 include complete experimental detailalong with accompanying physical data for intermediates and finalproducts. The chemistry leading to the final products of Examples 11-64,67 and 68 utilizes procedures similar to that of Examples 1-10, and ispresented in summary form along with physical data for the finalproducts. The compounds of Example 69 are prepared by analogy to thoseof Examples 1-68.

Temperatures are give in °C. unless otherwise specified. The UV data forthe carbapenem products usually includes the results of extinguishingthe bicyclic β-lactam-thieno ether chromophore with hydroxyamine (NH₂OH). This result is expressed as a percentage loss of the unextinguishedλ max or as the λ max and molar absorptivity of the extinguishedchromophore as determined by subtraiting the NH₂ OH treated curve fromthe extinguished curve. The final products are usually purified bychromatography on a column of Dowex 50W (sodium form) resin followed bychromatography on reverse phase, silica gel plates (RPS). Alternativepurification procedures include Chromatography on the neutralpolystyrene resins XAD-2 or SP207 (brominated polystryene), or by RPSchromatography only. The yields of crude and chromatographed productsare based on UV analysis of appropriate solutions using, in most cases,an assumed NH₂ OH extinguished molar absorptivity of 9500 for 100% pureproducts.

The following abbreviations are used in the examples are accompanyingschemes:

Ac=acetyl

iAm=isoamyl

Bu=butyl

DMAC=N,N-dimethylacetamide

DMF=N,N-dimethylformamide

Et=ethyl

EtOAc=ethyl acetate

LDA=lithium diisopropylamide

Me=methyl

MeCN=acetonitrile

Ms=methanesulfonyl

NBS=N-bromosuccinimide

Ph or φ phenyl

PNB=p-nitrobenzyl

iPr=isopropyl

THF=tetrahydrofuran

Ts=p-toluenesulfonyl

EXAMPLE 1 Sodium(5R,6S)-2-[2-(3-carboxylato-1-pyridiniun)ethylthio]-6-[1(R)-hydroxyethyl]carbapen-2-em-3-carboxylate##STR64##

Detailed procedures and physical data follow.

STEP 1 p-Nitrobenzyl nicotinate

A Suspension of nicotinic acid (5.00 g, 40.6 mmol) inN,N-dimethylformaide (40 ml) was treated with sodium methoxide (2.19 g,40.6 mmol). The resulting solution was treated with p-nitrobenzylbromide(8.77 g, 40.6 mmol) and heated at 50°, After heating 16 hrs the reactionwas allowed to cool to ambient temperature and diluted with ethylacetate (100 ml) and saturated aqueous sodium bicarbonate solution andfiltered. The organic fraction was separated and washed with water,brine, dried over anhydrous magnesium sulfate, filtered and evaporatedunder vacuum to a solid.

The crude product was chromatographed on a column of silica gel (E.Merck #7734) eluted with hexane-ethyl acetate (2:1). The productcrystallized from the eluting solvent upon standing and was recovered togive a white crystalline product, 2.85 g(29% yield).

NMR(CDCl₃)δ 5.56(s, CH₂), 7.63(dd, pyridyl H5), 7.80(d, aryl 2H),8.28(d, aryl 2H), 8.39(td, pyridyl H4), 8.87(dd, pyridyl H6), 9.20(d,pyridyl H2).

STEP 2 1-(2-Mercaptoethyl)-3-(p-nitrobenzyloxycarbonyl) pyridiniumnitrate

A solution of silver nitrate (1.39 g, 8.19 mmol) in acetonitrile (10 ml)was added to a solution of p-nitrobenzyl nicotinate (2.00 g, 8.19 mmol)in acetonitrile (50 ml). A tan precipitate formed. The mixture wasstirred at room temperature and treated with ethylene sulfide (0.49 ml,8.19 mmol). After 1.5 hours, the mixture was filtered to remove theprecipitate which dried under vacuum to an off-white solid. Thismaterial was suspended in ethanol (75 ml), treated with hydrogen sulfideover 5 minutes, and stirred an additional 5 minutes at room temperature.The mixture was centrifuged and filtered to remove the silver sulfide.The filtrate, on standing overnight at room temperature, deposited thetitle compound (0.30 g) as fine white needles.

NMR (DMSO-d₆)δ 2.72 (t, J=7 Hz, SH), 3.15 (q, J=7 Hz, SCH₂), 4.90 (t,J=7 Hz, NCH₂), 5.66 (s, CH₂ Ar), 7.87 (d, J=8 Hz, 2 ArH), 8.33 (d, J=8Hz, 2 ArH), 8.38 (m, pyridyl H5), 9.14 (d, J=8 Hz, pyridyl H4), 9.31 (d,J=6 Hz, pyridyl H6), 9.70 (s, pyridyl H2).

STEP 3 Sodium (5R,6S)-2-[2-(3-carboxylato-1-pyridinium)ethylthio]-6-[1(R)-hydroxyethyl]carbapen-`-em-3-carboxylate

A solution of p-nitrobenzyl(5R,6S)-2-(diphenylphosphono)oxy-6-[1(R)-hydroxyethyl]carbapen-2-em-3-carboxylate(175 mg, 0.30 mmol) and1-(2-mercaptoethyl)-3-(p-nitrobenzyloxycarbonyl)-pyridinium nitrate (120mg, 0.32 mmol) in anhydrous acetonitrile (3.0 ml) was cooled in anice-bath under a nitrogen atmosphere and treated withN,N-diisopropylethylamine (0.11 ml, 0.63 mmol). The resulting solutionwas left an ice-bath temperature overnight, then diluted withdiethylether (30 ml) and passed through a celite pad. The etherinsoluble oil and the residue left on the celite pad were dissolved in amixture of n-butanol (19 ml), ethylacetate (9 ml), water (19 ml), and0.5M pH 6.8 N-methyl morpholine-hydrochloric acid buffer (9 ml), treatedwith 20% palladium hydroxide on carbon (105 mg), and hydrogenated on aParr shaker at 40 psi for 1 hour. The mixture was centrifuged to removethe catalyst and the supernatant was washed with methylene chloride(2×25 ml). The aqueous phase was concentrated under vacuum and added toa column of Dowex 50W-X4 resin (sodium form, 200-400 mesh, 1.5×33 cm)which was eluted with deionized water in a cold room. The productcontaining fractions were located by UV, combined, and concentratedunder vacuum to ca. 2.5 ml. The solution was applied to four Analtech0.5 mm×20×20 cm RPS-F plates which were developed with water in a coldroom. The major UV visible band was removed and eluted with 4:1acetonitrile-water. The extracts were washed with hexane, concentratedunder vacuum, and lyophilized to provide the title compound (60.5 mg) asan amorphous, yellow solid.

IR (Nujol) 3350(br), 1755, 1645, 1610, 1580, 1250, 1135, 1072 cm⁻¹.

UV (H₂ O)λ max 270(ε 6040), 296(ε 6970) nm. UV (H₂ O+NH₂ OH)λ max ext.296(ε ext. 6250) nm.

NMR (D₂ O)δ 1.27(d, CH₃ CH), 2.94 and 3.11(two dd, CH₂), 3.33(dd, H6),3.40 and 3.58(two tq, SCH₂), 4.0l(dt, H5), 4.20(p, CH₃ CH), 4.8-4.9(m,CH₂ N), 8.10(t, pyridyl H5), 8.9-8.95(m, pyridyl H4,H6), 9.26(s, pyridylH2).

EXAMPLE 2 Sodium (1R,5S,6S)-2-[2-(4-carboxylato-1-pyridinum)ethylthio]-6-[1-(R)-hydroxyethyl]-l-methyl-carbapen-2-em-3-carboxylate##STR65##

Detailed procedures and physical data follow:

STEP 1 1-(2-mercaptoethyl)-4-carboxy-pyridinium nitrate

A suspension of isonicotinic acid (2.00g, 16.2 mmol) in water (20 ml)was adjusted to pH 6 with aqueous sodium hydroxide (2.5N). The resultingsolution was treated with a solution of silver nitrate (2.76 g, 16.2mmol) in water (5ml) to give a white suspension. Additional water (20ml) was added to facilitate stirring and the suspension was treated withethylene sulfide (1.06 ml, 17.8 mmol). After 1 hr the yellow suspensionwas filtered, the cake water washed, and resuspended in water (25 ml).The suspension was bubbled with hydrogen sulfide (5 min), stirred (5min), and filtered.

The filtrate was evaporated under vacuum to a yellow solid (1.57g, 38%).

NMR(D₂ O)δ3.17(t, J=6.4Hz, SCH₂), 4.83(t, J=6.4 Hz, NCH₂), 8.38(d, J=6.5Hz, pyridyl H3, H5), 8.98(d, J=6.5 Hz, pyridyl H2, H6).

STEP 2 Sodium(1R,5S,6S)-2-[2-(4-carboxylato-1-pyridinium)-ethylthio]-6-[1(R)-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate

A suspension of 1-(2-mercaptoethyl)-4-carboxypyridinium nitrate (26mg,0.10 mmol) and vinyl phosphate (75mg, 0.13 mmol) in N-ethylpyrrolidinone(0.50 ml) was cooled in an ice bath and treated withN,N-diisopropylethylamine (0.037 ml, 0.21 mmol). After 24 min thereaction solution was mixed with water (1.3 ml), pH 7.0 0.5MN-methylmorpholine-HCl buffer (1:0 ml), isoamyl alcohol (1 8 ml), and20% palladium hydroxide on carbon (34 mg) and hydrogenated on a Parrshaker.

After 1 hr the mixture was removed from the shaker, filtered, and theorganic phase discarded. The aqueous phase was washed withdichloromethane, concentrated and chromatographed on a Dowex50-X4 (Na⁺cycle) column eluted with water in the cold room (4°). The productsolution was isolated, concentrated, and chromatographed on three 1000micron thick (20×20 cm) RPS-F plates (Analtech) using 1.5% ethanol-wateras developing solvent. The desired product bands were isolated,extracted with acetonitrile-water (100 ml, 5:1), and this solutionwashed with hexane. The solution was concentrated under vacuum andlyophilized to afford the product as an off-white fluff (21.2 mg).

IR (Nujol) 3350(br), 1755, 1620, 1570, 1140 cm⁻¹.

UV (H₂ O)λ max 293(ε 7370)nm. UV (H₂ O+NH₂ OH)λ max ext. 297(ε ext.6280) nm.

NMR (D₂ O)ε 1.15(d, 1-CH₃), 1.28(d, CH₃ CHOH). 3.2-3.3(m, H1), 3.29 and3.57 (two td, SCH₂), 3.42(dd. H6). 3.97(dd. H5). 4.22(p. CH₃ CHOH).4.9-5.1(m, CH₂ N), 8.30(d, pyridyl H3, H5), 8.9l(d, pyridyl H2,H6).

EXAMPLE 3 Sodium(5R,6S)-6-[1(R)-hydroxyethyl]-2-[2-(4-sulfonatomethyl)-lyridinium)ethylthio]carbapen-2-em-3-carboxylate##STR66##

Detailed procedures and physical data follow:

STEP 1 Sodium 4-pyridylmethylsulfonate

A solution of 4-mercaptomethylpyridine (2.20 g, 17.6 mmol) inacetonitrile (8.0 ml) was added to a stirred solution of 40% peraceticacid-acetic acid (25 ml) at ice bath temperature. After addition thesolution was removed from the ice bath and stirred at room temperatureovernight. The solution was concentrated under vacuum to a white solidwhich was dissolved in water (1.5 ml) and adjusted to pH 9 with 2.5Naqueous sodium hydroxide. The resulting white suspension was filteredand the filtrate evaporated under vacuum to afford the title compound asa white solid (2.32 g).

NMR (D₂ O)δ 4.24 (s, CH₂), 7.50 (d, J=5.4 Hz, ArH), 8.53 (d, J=5.4 Hz,ArH).

STEP 2 1-(2-Mercaptoethyl)-4-sulfomethylpyridinium hydroxide, inner salt

A solution of silver nitrate (1.31 g, 7.68 mmol) in water (4 ml) wasadded to a stirred solution of sodium 4-pyridylmethylsulfonate (1.50 g,7.68 mmol) in water (15 ml). The resulting hazy solution was treatedwith ethylene sulfide (0.51 ml, 8.58 mmol) added dropwise over 2minutes. The resulting gummy mixture was let stand at room temperature30 minutes and the supernatant decanted. The residue was mixed withwater (10 ml) and vigorously bubbled with hydrogen sulfide for 10minutes. The mixture was vigorously stirred an additional 1 hour and thesilver sulfide precipitate removed by centrifugation. The supernatantwas concentrated under vacuum to ca. 5 ml and charged onto a column ofDowex 50W-X4 (hydrogen form, 200-400 mesh, 1.5×33 cm). The column waseluted with water at 6.0 ml fractions/2.0 minutes. Fractions 19 to 27were combined and evaporated under vacuum to an off-white solid. Thesolid was mixed with a few mls of methanol and filtered to afford thetitle compound as an off-white solid (303 mg).

NMR (D₂ O) δ 3.16 (t, J=6.4 Hz, SCH₂), 4.52 (s, CH₂ SO₃), 4.79 (t, J=6.4Hz, NCH₂), 8.12 (d, J=6.2 Hz, pyridyl H3, H5), 8.86 (d, J=6.2 Hz,pyridyl H2, H6).

Anal. Calc'd for C₈ H₁₁ NO₃ S₂ : C, 41.18; H, 4.75; N, 6.00; S, 27.48.Found: C, 41.32; H, 4.77; N, 6.07; S, 27.17.

STEP 3 Sodium(5R,6S)-6-[1(R)-hydroxyethyl]-2-[2-(4-sulfonatomethyl-1-pyridinium)ethylthio]carbapen-2-em-3-carboxylate

A solution of p-nitrogenzyl(5R,6S)-2-(diphenylphosphono)oxy-6[1(R)-hydroxyethyl]-carbapen-2-em-3-carboxylate(300 mg, 0.517 mmol) and 1-(2-mercaptoethyl)-4-sulfomethylpyridiniumhydroxide inner salt (121 mg, 0.517 mmol) in tetrahydrofuran (2.0 ml)and water (0.65 ml) was treated at ice bath temperature withN,N-diisopropylethylamine (0.090 ml, 0.517 mmol). After stirring 10 min,the reaction solution was diluted with n-butanol (10.0 ml), ethylacetate (5.0 ml), water (10.0 ml), and 0.5M pH 6.8 N-methylmorpholine -hydrochloric acid buffer (5.0 ml), mixed with 10% palladium on carbon(125 mg), and hydrogenated on Parr shaker at 45 psi for 75 min Thecatalyst was removed by filtration through a prewashed celite pad, andthe filtrate washed with methylene chloride. The aqueous phase wasconcentrated under vacuum to ca. 7.5 ml and charged onto a column ofDowex 50W-X4 (sodium form, 200-400 mesh, 1.5×33 cm). The column waseluted with water in the cold room (4°) at 6.0 ml fractions/2.0 min.Fractions 4 to 8 were combined and concentrated under vacuum to ca. 8 mland lyophilized to powder. This material was chromatographed on five 1.0mm×20×20 cm Analtech RPS-F plates using water as a developing solvent ina cold room (4°). The major uv visible band on each plate at Rf 0.3 0.5was removed and eluted with 4:1 acetonitrile-water. The eluant waswashed with hexane, concentrated under vacuum to ca. 20 ml, filteredthrough an Acrodisc (Gelman, 0.2 micron CR) and lyophilized to affordthe title compound (100.3 mg) as an amorphous white powder.

IR (Nujol) 3400 (br), 1740, 1638, 1582, 1520, 1231, 1190, 1036 cm⁻¹.

UV (H₂ O) λ max 219(ε 11,400), 260(ε 6,320), 296(ε 7,250)nm.

NMR (D₂ O) δ 1.20(d CH₃ CH), 2.94 and 3.08(two dd, CH₂), 3.3-3.53(m,SCH₂), 3.35(dd, H6), 4.07(dt, H5), 4.20(p, CH₃ CH), 4.52(s, CH₂ SO₃),4.6-4.8(m, CH₂ N), 8.11(d, pyridyl H3,H5), 8.85(d, pyridyl H2,H6).

EXAMPLE 4 Sodium(1R,5S,6S)-6-[1(R)-hydroxyethyl]-2-[2-(4-sulfonatomethyl-1-pyridinium)ethylthio)-1-methylcarbapen-2-em-3-carboxylate##STR67##

Detailed procedures and physical data follow:

STEP 1 Sodium(1R,5S,6S)-6-[(1R)-hydroxyethyl]-2-[2-(4-sulfonatomethyl)-1-pyridinium)ethylthio]-1-methylcarbapen-2-em-3-carboxylate

A solution of p-nitrobenzyl(1R,5R,6S)-2-(diphenylphosphono)oxy-6-[(1R)-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate(200 mg, 0.336 mmol) and 1-(2-mercaptoethyl)-4 sulfomethylpyridiniumhydroxide inner salt (82 mg, 0.353mmol) in tetrahydrofuran (1.5 ml) andwater (0.5 ml) was treated at room temperature withN,N-diisopropylethylamine (0.062 ml, 0.353mmol). After stirring 11 min,the reaction solution was diluted with n-butanol (6.7 ml), ethyl acetate(3.4 ml), water (6.7 ml), and 0.5M pH 6.8N-methylmorpholine-hydrochloric acid buffer (3.4 ml), mixed with 20%palladium hydroxide on carbon (75 mg). and hydrogenated on a Parr shakerat 42 psi for 75 min. The catalyst was removed by filtration through acelite pad, and the filtrate washed with methylene chloride. The aqueousphase was concentrated under vaccuum to ca. 10 ml and charged onto acolumn of Dowex 50W-X4(sodium form, 200-400 mesh, 1.5×33 cm). The columnwas eluted with water in the cold room (4°) at 4.0 ml fractions/2.0 min.Fractions 4 to 10 were combined and concentrated under vacuum to ca. 8ml and lyophilized to powder. This material was chromatographed on four1.0 mm ×20×20 cm Analtech RPS-F plates using 2% ethanol water as adeveloping solvent in a cold room (4°). The uv visible band on eachplate at Rf 0.4-0.5 was removed and eluted with 4:1 acetonitrile-water.The eluant was washed with hexane, concentrated under vacuum to ca. 4ml, filtered through an Acrodisc (Gelman, 0.45 micron CR) andlyophilized to afford the title compound (35.3 mg) as an amorphous whitepowder.

IR (Nujol) 3400(br), 1740, 1640, 1590, 1235, 1185, 1040 cm⁻¹.

UV (H₂ O) λ max 229(ε 11600), 260(ε 6020), 298(ε 6940)nm. UV (H₂ O+NH₂OH) λ max ext. 297nm (ε ext. 6130)nm.

NMR (D₂ O) δ 1.14(d, 1-CH₃), 1.28(d, CH₃ CHOH), 3.22(dq, H1), 3.29 and3.56 (two td, SCH₂), 3.41(dd, H6), 3.99(dd, H5), 4.29(p, CH₃ CHOH),4.53(s, CH₂ SO₃), 4.7-4.9(m, CH₂ N), 8.11(d, pyridyl H3,H5), 8.83(d,pyridyl H2,H6).

EXAMPLE 5 Sodium(5R,6S)-2-[2-(3-chloro-4-sulfonatomethyl-1-pyridinium)ethylthio]-6-[1(R)-hydroxyethyl]carbapen-2-em-3-carboxylate##STR68##

Detailed procedures and physical data follow:

STEP 1 3-Chloro-4-pyridinecarboxaldehyde

An ice cold solution of N,N diisopropylamine (66.0 ml, 0.471 mol) infreshly distilled tetrahydrofuran (1190 ml) in a dry three neck flaskfitted with a dropping funnel, thermometer, and septum was treateddropwise with n-butyl lithium in hexane (2.6M, 185 ml, 0 462 mol). Thesolution of lithium diisopropylamide was aged at 0° for 30 min, thencooled in a chloroform-dry ice bath to -60° and treated with3-chloropyridine (41.9 ml, 0.440 mol) added over 5 min. A brown mixtureslowly developed.

After 1 hr from the completion of addition the brown mixture was cooledin an acetone-dry ice bath to an internal temperature of -70° andtreated with ethyl formate (40.0 ml, 0.495 mol) added neat over 1 min.The internal temperature rose to -62°. The brown mixture yielded to abrown solution which was stirred 30 min at acetone-dry ice bathtemperature (internal temperature after 30 min -70°) then treated withaqueous 3N hydrochloric acid (154 ml, 0.462 mol) and allowed to warm toambient temperature.

The reaction was concentrated under vacuum to a viscous oil and mixedwith ethyl acetate (250 ml). The organic phase was recovered and theaqueous phase extracted with ethyl acetate (200 ml). The combinedorganic extracts were washed with brine, dried over anhydrous magnesiumsulfate, filtered, and concentrated under vacuum to a brown semi-solid(63.23 g).

The entire crude product was absorbed onto silica gel (60g, E. Merck#7734) and applied to a silica gel column (125g, column 5.5 cm ×8.7 cmdiam.) packed in 3:1 hexane-ethyl acetate. The column was eluted withthe same solvent system at maximum flow rate. The product was collectedas a light yellow solid (43.80 g, 70%).

NMR(CDCl₃) δ 7.71(d, J=4.9 Hz, Ar5H), 8.70(d, J=4.9 Hz, Ar6H), 8.80(s,Ar2H), 10.50(s, CHO).

mp 58.0°-58.5°

Microanalytical: Calc'd C, 50.91; H, 2.85; N, 9.90; Found C, 50.63; H,2.78; N, 9.66.

STEP 2 3-Chloro-4-hydroxymethylpyridine

A suspension of 3-chloro-4-pyridinecarboxaldehyde (43.80g, 0.310mol) inethanol (200 ml) was cooled in an ice bath and treated with powderedsodium borohydride (5.85 g, 0.155 mol) added in portions overapproximately 2 min. The resulting solution was removed from the icebath and stirred at ambient temperature. After 1 hr the solution wasrecooled in an ice bath and treated with acetone (22 ml) to decomposeexcess borohydride. The solution was again removed from the ice bath andstirred at ambient temperature. After 30 min the reaction solution wasevaporated under vacuum to a viscous oil.

The oil was partitioned between ethyl acetate (250 ml) and a saturatedaqueous solution of sodium bicarbonate (50 ml). The organic phase wasrecovered and the aqueous phase extracted with additional ethyl acetate(150 ml). The combined organic phases were washed with brine, dried overanhydrous magnesium sulfate, filtered, and evaporated under vacuum to awhite solid (54.90g). The crude product was dissolved in hot toluene(500 ml) and crystallized upon cooling to provide the desired product(33.90 g, 76%).

NMR(CDCl₃) δ 4.67(s, CH₂ OH), 7.37(d, J=5.3Hz, Ar5H), 8.35(d, J=5.3Hz,Ar6H), 8.36(s, Ar2H).

mp 114°-115°

Microanalytical: Calc'd C, 50.19; H, 4.21; N, 9.76; Found C, 50.53; H,4.22; N, 9.71.

STEP 3 3-Chloro-4-chloromethylpyridine hydrochloride

Solid 3-chloro-4-hydoxymethylpyridine (33.8 g, 0.235 mol) was addedcautiously over 8 min to stirred thionyl chloride (72 ml, 0.706 mol)cooled in an ice bath and under a stream of N₂. After addition theyellow solution was heated in an oil bath at 50° and protected under atube of Drierite. After 30 min the solution was removed from the oilbath, allowed to cool to ambient temperature, and poured into a flask ofstirred anhydrous ether (1,000 ml).

The precipitate was recovered by filtration, ether washed, and the solidvacuum dried to afford the product as an off-white solid (45.77q, 98%).

NMR(DMSO-d₆) δ 4.88(s, CH₂ Cl), 7.73(d, J=4.9 Hz, Ar5H), 8.62(d, J=4.9Hz, Ar6H), 8.76 (s, Ar2H).

STEP 4 3-Chloro-4-sulfomethylpyridine

A suspension of sodium sulfite (75.90 g, 0.602 mol) in a solution ofwater (240 ml) and ethanol (60 ml) was treated at ambient temperaturewith solid 3-chloro-3-chloromethylpyridine hydrochloride (59.77g, 0.301mol). The resulting mixture was heated in an oil bath to reflux.

After 2hr the resulting light yellow solution was removed from the bathand allowed to cool to ambient temperature and evaporated under vacuumto a semi-solid. The crude sodium salt was mixed with concentratedhydrochloric acid (100 ml) and filtered. The cake was washed with anadditional amount (100 ml) of concentrated acid. The filtrate depositedadditional salt and was refiltered.

The acidic filtrate was concentrated under vacuum to an orange coloredsemi-solid. The solid was again suspended in concentrated hydrochloricacid (50 ml) and refiltered and the salt cake washed with concentratedacid. The filtrate was concentrated under vacuum to a semi-solid andmixed with glacial acetic acid (600 ml). The mixture was heated toreflux and filtered hot. The recovered solid was washed with a smallportion of acetic acid and vacuum dried to produce a lightly pinkcolored solid (41.10 g, 66%).

NMR(D₂ O) δ 4.64(s, CH₂ SO₃), 8.13(d, J=5.5Hz, Ar5H), 8.71(d, J=5.5Hz,Ar6H), 8.96(s, Ar2H).

STEP 5 1-(2-Acetylthioethyl)-3-chloro-4-sulfomethylpyridinium hydroxide,inner salt

A suspension of 3-chloro-4-sulfomethylpyridine (19.0 g, 0.092 mol) inDMF (100 ml) was treated with N,N diisopropylethylamine (16.8 ml, 0.096mol) and 2-bromoethyl thiolacetate (16.0 ml, 0.137 mol). The resultingpale yellow solution was heated in an oil bath at 100° for 2 hrs, thentreated with additional alkylating agent (7.5 ml, 0.064mol. 2.2 equiv.total) and heated overnight at 100°.

After 19 hrs heating, a dark suspension had formed and reverse phase TLC(Analtech RPS-F, H₂ O, UV) showed no starting material. The mixture wascooled in an ice bath for 30 mins and in a freezer for 30 mins, thenfiltered. The filter cake was washed with cold ethanol (100 ml) anddried under a stream of N₂ to afford the crude product (22g) as a lightyellow solid.

This material in DI H₂ O (100 ml) was mixed with activated charcoal,heated to 35° on a steam bath, and filtered through a pad of Solka-Flocusing additional rinse H₂ O (5 ml). The aqueous filtrate wasconcentrated under vacuum to remove 60 ml of H₂ O, then diluted withethanol (250 ml) and seeded. The mixture was kept at ambient temperaturefor 10 mins, followed by cooling in an ice bath for 30 mins and in afreezer for 30 mins. The product was collected, washed with ethanol (100ml), and dried under a N₂ stream to provide the title compound as paleyellow crystals (21.5 g).

NMR(D₂ O) δ 2.41(s, SCOCH₃), 3.63(t, J=6.0 Hz, SCH₂), 4.91(t, J=6.0 Hz,CH₂ N), 4.75(s, CH₂ SO₃), 8.28(d, J=6.0 Hz, Ar5H), 8.94(d, J=6.0 Hz,Ar6H), 9.32(s, Ar2H).

STEP 6 1-(2-Mercaptoethyl)-3-chloro-4-sulfomethylpyridinium hydroxide,inner salt

A solution of the N-acetylthioethyl -pyridinium salt (18.5g, 0.06 mol)in 4N HCl (100 ml) was heated in a 40°oil bath and under a N₂ atm for 18hrs. The solution was evaporated under vacuum and the residue twicestripped with ethanol to give an off-white solid. This material wassuspended in ethanol, filtered, and dried under a N₂ stream to providethe product (14.0 g, 87.5%) as a white solid.

NMR(D₂ O) δ 3.20(t, J=6.0 Hz, SCH₂), 4.71(s, CH₂ SO₃), 4.83(t, J=6.0 Hz,CH₂ N), 8.25(d, J=6.0 Hz, Ar5H), 8.88(d, J=6.0 Hz, Ar6H), 9.23(s, Ar2H).

Microanalytical: Calc'd C, 35.89; H, 3.76; N, 5.23; S, 23.95; Found C,35.76; H, 3.82; N, 5.18; S, 24.28.

STEP 7 p-Nitrobenzyl(5R,6S)-2-[2-(3-chloro-4-sulfonatomethyl-1-pyridinium)ethylthio]-6-[1-(R)-hydroxyethyl]carbapen-2-em-3-carboxylate

A suspension of vinyl phosphate (2.00 g, 3.45 mmol) and finely powderedmercaptan (968 mg, 3.62 mmol) in anhydrous DMF (6.9 ml) was cooled in anice bath under a N₂ atmosphere. The suspension was treated with iPr₂ NEt(0.630 ml, 3.62 mmol) added dropwise over 40 min. After base addition athick, light tan colored suspension resulted which was mixed with EtOH(75 ml) and filtered. The filter cake was washed with EtOH (2×50 ml)followed by Et₂ O (50 ml) and dried under a N₂ stream. The final productwas vacuum dried to afford an off-white crystalline solid (1.83 g,88.8%).

NMR(DMSO-d₆) δ 1.16(d, CH₃ CHOH), 3.2-3.6 (m, CH₂), 3.40(dd, H6),3.57(m, SCH₂), 3.98(m, CH₃ CHOH), 4.19(m, H5), 4.22(s, CH₂ SO₃), 4.80(m,CH₂ N), 5.13(d, OH), 5.40(ABq, CH₂ Ar), 7.70 and 8.24 (two d's, ArH),8.20(d, pyr H5), 8.95(d, pyr H6), 9.34(s, pyr H2).

STEP 8 Sodium(5R,6S)-2-[2-(3-chloro-4-sulfonatomethyl-1-pyridinium)ethylthio]-6-[1(R)-hydroxyethyl]carbapen-2-em-3-carboxylate

The crystalline ester (1.25 g, 2.09 mmol) was added to a mixture of nbutanol (5 ml), ethyl aceta (25 ml), and water (100 ml) to give a freelyflowing suspension in the upper phase. Solid NaHCO₃ (175 mg, 2.09 mmol)and 10% Pd/C (500 mg) were added and the mixture was hydrogenated in a450 ml Paar flask at 45 psi for 2 hrs ( the ester dissolved within thefirst hour).

The reaction mixtures from two identical runs were combined and filteredthrough a pad of solka-floc. The aqueous portion of the filtrate wasseparated, washed with ethyl acetate (200 ml), and concentrated undervacuum to 42 ml. The concentrate was added to an ice water jacketed,prewashed column of SP-207 resin (2.5 cm ×25.5 cm, 125 cc) which waseluted initially with DI water and then with 4% methanol in water at arate of 5 ml/min. 25 Ml fractions were collected. The progress of thechromatography was monitored by UV and NMR spectroscopy. The results aretabulated below.

    ______________________________________                                        Fractions                                                                            Eluant     Volume    Weight ε ext 300 nm                       ______________________________________                                        1-5    H.sub.2 O  125    ml   --     --                                       6      H.sub.2 O  25     ml   0.056 g                                                                              6216                                     7      H.sub.2 O  25     ml   0.083 g                                                                              6819                                     8      H.sub.2 O  25     ml   0.105 g                                                                              6653                                     9-27   H.sub.2 O  475    ml   1.080 g                                                                              6931                                     28-45  4% CH.sub.3 OH                                                                           450    ml   0.234 g                                                                              6540                                     46-63  4% CH.sub.3 OH                                                                           450    ml   0.048 g                                                                              6242                                     ______________________________________                                    

Fractions 9-27 were combined, concentrated under vacuum to 100 ml, andlyophilyzed to afford the product (1.080 g) as a yellow, amorphoussolid. Other fractions were similarly processed to give the weightsshown in the table. Fractions 9-27 gave the cleanest product asevidenced by UV and ¹ H NMR spectroscopy.

NMR (D₂ O) δ 1.29 (d, CH₃ CH), 3.00 and 3.13 (two dd, CH₂), 3.38 (dd,H6), 3.36 and 3.56 (two td, SCH₂), 4.12 (dt, H5), 4.22 (dq, CH₃ CH),4.69 (s, CH₂ SO₃), 4.88 (m, CH₂ N), 8.23 (d, pyr H5), 8.84 (d, pyr H6),and 9.18 (s, pyr H2).

IR (nujol) νmax 3400 (br), 1740, 1630, 1585, 1230, 1190, and 1035 cm⁻¹.

UV (H₂ O) λ max 300 (sh, ε 8570), 285 (ε 10,330), 240 (ε 10,040) nm; UV(H₂ O+NH₂ OH) λ max 276 (ε 4,830) nm; λ max ext 297 (ε ext 7050) nm.

EXAMPLE 6 Sodium(5R,6S)-6-[1(R)hydroxyethyl]-2-[2-[4-(2-sulfonatoethyl)-1-pyridinium]-ethylthio-carbapen-2-em-3-carboxylate ##STR69##

Detailed procedures and physical data follow:

STEP 1 1-(2-mercaptoethyl)-4-(2-sulfoethyl)pyridinium hydroxide innersalt

A solution of silver nitrate (1.84 g, 10.6 mmol) in water (5 ml) wasadded to a stirred aqueous solution (20 ml) of 4-pyridine ethanesulfonic acid (2.00 g, 10.6 mmol) which had been adjusted to pH 7 by theaddition of aqueous 2.5N sodium hydroxide (3.0 ml). The solution wascooled in an ice-water bath and ethylene sulfide (0.71 ml, 11.8 mmol)added. The resulting mixture was let stand 45 minutes at ice-bathtemperature and the upper clear phase decanted. The gummy solid wasmixed with water (20 ml) and vigorously bubbled with hydrogen sulfidefor 15 minutes. After stirring an additional 20 minutes, the mixture wasfiltered through a celite pad to remove silver sulfide and the filtratewas evaporated under vacuum to provide crude title compound as a whitesemi-solid (1.00 g).

STEP 2 Sodium(5R,6S)-6-[1(R)hydroxyethyl]2-[2-[4-(2-sulfonatoethyl(-1-pyridinium]-ethylthio]-carbapen-2-em-3-carboxylate

A solution of p-nitrobenzyl(5R,6S)-2-(diphenylphosphono)oxy-6-[1R)-hydroxyethyl]-carbapen-2-em-3-carboxylate(200 mg, 0.344 mmol) and 1-(2-mercaptoethyl)-4-(2-sulfoethyl)pyridiniumhydroxide inner salt 89 mg, 0.362 mmol) in tetrahydrofuran (1.0 ml) andwater (0.3 ml) was treated at room temperature withN,N-diisopropylethylamine (0.063 ml, 0.362 mmol). After stirring 10minutes, the reaction solution was diluted with n-butanol (6.8 ml),ethyl acetate (3.4 ml), water 6.8 ml), and 0.5M pH 6.8N-methyl-morpholine-hydrochloric acid buffer (3.4 ml), mixed with 20%palladium hydroxide on carbon (80 mg), and hydrogenated on a Parr shakerat 44 psi for 75 minutes. The catalyst was removed by filtration throughan Acrodisc (Gelman, 0.45 micron CR), and the filtrate washed withmethylene chloride. The aqueous phase was concentrated under vacuum toca. 8.5 ml and charged onto a column of Dowex 50W-X4 (sodium form,200-400 mesh, 1.5×35 cm). The column was eluted with water in the room(4°) at 4.0 ml fractions/1.5 minutes. Fractions 6 to 13 were combinedand concentrated under vacuum to ca. 9 ml and lyophilized to powder.This material was chromatographed on three 1.0 mm 20×20 cm AnaltechRPS-F plates using 2% ethanol-water as a developing solvent in a coldroom (4°). The major UV visible band on each plate at Rf 0.4-0.6 wasremoved and eluted with 4:1 acetonitrile-water. The eluant was washedwith hexane, concentrated under vacuum to ca. 7 ml, filtered through anAcrodisc (Gelman, 0.45 micron CR) and lyophilized to afford the titlecompound (45 mg) as an amorphous white powder.

IR (Nujol) 3375(br), 1745, 1640, 1590, 1520, 1175, 1040 cm⁻¹.

UV(H₂ O) λ max 223(ε 10510), 255(ε 5670), 295(ε 7240)nm. UV(H₂ O+NH₂ OH)λ max ext. 296 (ε ext. 6720)nm. NMR (D₂ O) δ 1.28(d, CH₃ CH), 2.94 and3.10 (two dd, CH₂), 3.35(dd, H6), 3.3-3.5 (m, CH₂ CH₂ SO₃), 4.05(dt,H5), 4.22(p, CH₃ CH), 8.02(d, pyridyl H3,H5), 8.76(d, pyridyl H2, H6).

EXAMPLE 7 Sodium(1R,5S,6S)-6-[1(R)-hydroxyethyl]-2-[2-[4-(2-sulfonatoethyl)-1-pyridinium]ethylthio-1-methylcarbapen-2-em-3-carboxylate##STR70##

Detailed procedures and physical data follow:

STEP 1 Sodium(1R,5S,6S)-6[1(R)-hydroxyethyl]-2-[2-4-(2-sulfonatoethyl)-1-pyridinium]ethylthio-1-methylcarbapen-2-em-3-carboxylate

A solution of p-nitrobenzyl(1R,5R,6S)-2-(diphenylphosphono)oxy-6-[1(R)-hydroxyethyl]-1-methylcarbapen-2-em3-carboxylate (200 mg, 0.336 mmol) and1-(2-mercaptoethyl)-4-(2-sulfoethyl)pyridinium hydroxide inner salt (83mg, 0.336 mmol) in tetrahydrofuran (2.0 ml) and water (1.0 ml) wastreated at room temperature with N,N-diisopropylethylamine (0.062 ml,0.353 mmol). After stirring 15 min, the reaction solution was dilutedwith n-butanol (6.7 ml), ethyl acetate (3.4 ml), water (6.7 ml), and0.5M pH 6.8 N-methylmorpholine-hydrochloric acid buffer (3.4 ml), mixedwith 20% palladium hydroxide on carbon (75 mg), and hydrogenated on aParr shaker at 43 psi for 75 min. The catalyst was removed by filtrationthrough a celite pad, and the filtrate washed with methylene chloride.The aqueous phase was concentrated under vaccuum to ca. 8 ml and chargedonto a column of Dowex 50W-X4(sodium form, 200- 400 mesh, 1.5×33 cm).The column was eluted with water in the cold room (4°) at 5.0 mlfractions/2.0 min. Fractions 4 to 10 were combined and concentratedunder vacuum to ca. 13 ml and lyophilized to powder. This material waschromatographed on five 0.5 mm×20×20 cm Analtech RPS-F plates using 1%ethanol/water as a developing solvent in a cold room (4°). The major uvvisible band on each plate at Rf 0.3-0.5 was removed and eluted with 4:1acetonitrile-water. The eluant was washed with hexane, concentratedunder vacuum to ca. 6 ml, filtered through an Acrodisc (Gelman,0.45micron CR) and lyophilized to afford the title compound (82.1 mg) asan amorphous white powder.

IR (Nujol) 3375(br) 1745, 1660, 1590, 1220, 1180, 1150, 1040 cm⁻¹.

UV (H₂ O) λ max 255(ε 5,350), 294(ε 7,200)nm. UV (H₂ O+NH₂ OH) λ maxext. 297nm (ε ext. 6,630)nm.

NMR (D₂ O) δ 1.13(d, CH₃ CH), 1.28(d CH₃ CHOH), 3.1-3.7(m, SCH₂, CH₂ CH₂SO₃, H1,H6), 3.94(dd, H5), 4.23(p, CH₃ CHOH), 4.9-5.1(m, CH₂ N), 8.01(d,pyridyl H3,H5), 8.73(d, pyridyl H2,H6).

EXAMPLE 8 Sodium(1R,5S,6S)-6-[1(R)-hydroxyethyl]-2-[2-(4-sulfonatoaminomethyl-1-pyridinium)ethylthio]-1-methylcarbapen-2-em-3-carboxylate ##STR71##

Detailed procedures and physical data follow:

STEP 1 N-(4-pyridylmethyl)sulfamic acid

A suspension of 4-(aminomethyl)pyridine (5.00 g, 46.2 mmol) and sulfurtrioxide pyridine complex (9.20 g, 57.8 mmol) in p-dioxane (200 ml) wasstirred at ambient temperature. After 1 hr. the suspension was mixedwith water (200 ml). filtered, and concentrated under vacuum to a solid.The solid was suspended in water (20 ml), filtered, washed with water,and vacuum dried. The crude product was crystallized from hot water,washed with water, followed by methanol, and vacuum dried to afford awhite crystalline product (1.02 g, 12%).

m.p. 227.0°-227.5°

Microanalytical: Calc'd C, 38.29; H, 4.28; N, 14.88; S, 17.04; Found C,38.26; H, 4.28; N, 14.85; S, 16.80.

STEP 2 1-(2-mercaptoethyl)-4-sulfoaminomethylpyridinium hydroxide, innersalt

A suspension of N-(4-pyridylmethyl)sulfamic acid (800 ml, 4.25 mmol) inwater (5.0 ml) was adjusted to pH 7.0 with aqueous sodium hydroxidesolution (2.5N). The resulting solution was treated with a solution ofsilver nitrate (723 ml, 4.25 mmol) in water (3.0 ml) to give a whitesuspension. Additional water (5.0 ml) was added to facilitate stirringand the mixture was treated with ethylene sulfide (0.280 ml, 4.67 mmol).

After 10 min the supernatant was decanted and the gum resuspended inwater and bubbled with hydrogen sulfide. After 10 min bubbling wasstopped and the mixture stirred at ambient temperature 1 hr andfiltered.

The filtrate was concentrated under vacuum and chromatographed on aDowex50-X4 (H⁺ cycle) column eluted with water. The eluate wasconcentrated under vacuum to a paste which was mixed with 2-propanol (5ml), filtered, 2-propanol washed, and vacuum dried to afford the productas a white solid (0.34 g, 32%).

m.p. 191°-192°

Microanalytical: Calc'd C, 38.69; H, 4.87; N, 11.28; S, 25.82; Found C,38.63; H, 4.93; N, 11.31; S, 25.75.

NMR(D₂ O) δ 3.15(t, J=6 Hz, SCH₂). 4.48(s, CH₂ NH), 4.75 (t. J=6 Hz,NCH₂), 8.11(d, J=6.9 Hz, pyridyl H3, H5), 8.79(d, J=6.9 Hz, pyridyl H2,H6).

STEP 3 Sodium(1R,5S,6S)-6-[1(R)-hydroxyethyl]-2-[2-(4-sulfonatoamino-methyl-1-pyridinium)ethylthio]-1-methylcarbapen-2-em-3-carboxylate

A suspension of 1-(2-mercaptoetyl)-4-sulfoaminomethylpyridiniumhydroxide, inner salt (84 mg, 0.34 mmol) and vinyl phosphate (200 mg,0.34 mmol) in tetrahydrofuran (2.0 ml) and water (0.68 ml) was cooled inan ice bath and treated with N,N-diisopropylethylamine (0.124 ml, 0.70mmol). After 15 min the solution was mixed with n-butanol (6.7 ml).ethyl acetate (3.9 ml), water (6.7 ml), pH 7.0 N-methylmorpholine-HClbuffer (0.5M, 3.9 ml). and 10% palladium on carbon (80 ml) andhydrogenated on a Parr shaker at 45 psi H₂. After 1.25 hr the mixturewas removed from the shaker, filtered, the aqueous phase isolated, andwashed with methylene chloride.

The concentrated aqueous phase was chromatographed on a Dowex 50-X4 (Na⁺cycle) column eluted with water in the cold room (4°). The productsolution was isolated, concentrated, and chromatographed on three 1,000micron thick (20×20 cm) RPS-F plates (Analtech) developed in water. Thedesired product bands were isolated, extracted with acetonitrile-water(100 ml, 5:1), and this solution washed with hexane. The solution wasconcentrated under vacuum and lyophilized to afford the product as anoff-white fluff (87.8 mg).

IR (Nujol) 3350(br), 1748, 1640, 1585, 1180, 1038 cm⁻¹.

UV (H₂ O) λ max 219(ε 8730), 257(ε 5710), 295(ε 6960) nm.

UV (H₂ O+NH₂ OH) λ max. ext. 297(ε ext. 6360) nm.

NMR (D₂ O) δ 1.13(d, 1-CH₃), 1.28(d, CH₃ CHOH), 3.21(qd, H1), 3.28(td,SCHaHb), 3.41(dd, H6), 3.54(ddd, SCHaHb), 3.94(dd, H5), 4.24(p, CH₃CHOH), 4.49(s, CH₂ NH). 4.7-4.9(m, CH₂ N), 8.09(d, pyridyl H3,H5),8.76(d, pyridyl H2, H6)

EXAMPLE 9 Sodium(5R,6S)-6-[1(R)-hydroxyethyl]-2-[2-[4-[N-(2-thiazolyl)-sulfamoylatomethyl]-1-pyridinium]ethylthio]carbapen-2-em-3-carboxylate##STR72##

Detailed procedures and physical data follow:

STEP 1 4-[N-(2-Thiazolyl)sulfamoylmethyl]pyridine

A suspension of finely ground 4-pyridylmethane sulfonic acid (2 g) andphosphorous pentachloride (2.5 g) in trifluoromethanesulfonic anhydride(40 ml) was refluxed with stirring for 16 hours. The product sulfonylchloride formed a heavy oily layer. The excess solvent was decanted offand the residue blown with nitrogen for a few minutes then pumped undervacuum until solidified. The solid sulfonyl chloride intermediate wasdissolved in anhydrous acetonitrile (60 ml) and added dropwise over 15minutes to a stirred solution of 2-aminothiazole (5 g) in acetonitrile(50 ml) at -15°. After 30 minutes the mixture was allowed to warm toroom temperature and the product was filtered. The filter case wasdissolved in hot 95% ethanol (60 ml) and the solution concentrated tohalf volume and chilled. The crystalline product was collected and driedto afford 1.04 g of a solid.

mp softens 195°, dec. 206°.

NMR(D₂ O) δ 4.71(s, CH₂ SO₃), 6.67(d, thiazolyl H5), 7.07(d, thiazolylH4), 8.01(d, pyridyl H3 and H5), 8.65(d, pyridyl H2 and H6).

STEP 2 1-(2-Mercaptoethyl)-4-[N-(2-thiazolyl)sulfamoylmethyl]pyridiniumhydroxide, inner salt

To a stirred solution of 4-[N-(2-thiazolyl)sulfamoylmethyl]pyridine (150mg, 0.59 mmol) in 1:1 acetonitrile-water (4 ml) at 0° was added silvernitrate (100 mg, 0.59 mmol). After 10 minutes, ethylene sulfide (0.036ml, 0.6 mmol) was added and the mixture was stirred at 0° for one hour.The solvents were removed under vacuum and the residual yellow solid wastriturated with water and filtered. The solid was resuspended in water(15 ml) and stirred while passing in a slow stream of hydrogen sulfidefor 15 minutes. The silver sulfide was removed by filtration and thenitrogen. The solution was adjusted to pH 6.7 with sodium bicarbonatethen evaporated under vacuum to afford the crude product as a resin (180mg). NMR shows approximately 80% of the desired product.

NMR(D₂ O) δ 3.2(t, CH₂ S), 6.9 and 7.26(two d, thiazolyl H5 and H4),8.24(pyridyl H3 and H5), 8.96(pyridyl H2 and H6).

STEP 3 Sodium(5R,6S)-6-[1(R)-hydroxyethyl]-2-[2-[4-[N-(2-thiazolyl)sulfamoylatomethyl]-1-pyridinium]ethylthio]carbapen-2-em-3-carboxylate

To a stirred solution of1-(2-mercaptoethyl)-4-[N-(2-thiazolyl)sulfamoylmethyl]pyridiniumhydroxide inner salt (113 mg, 0.3 mmol) in DMM (2 ml) at 0° was addedthe solid bicyclic vinyl phosphate (163 ml, 0.3 mmol) followed byN,N-diisopropylethylamine (0.08 ml, 0.45 mmol) dropwise over 2 minutes.The solution was stirred at 0° for 15 minutes then precipitated ontocelite by the addition of ethyl ether (90 ml). The solids were filteredand washed with ether. The filter cake was eluted with 1:1tetrahydrofuran-water (30 ml) and the filtrate collected in ahydrogenation bottle. Sodium bicarbonate (42 mg, 0.5 mmol) and 10% Pd/Ccatalyst were added and the mixture was shaken under hydrogen at 45 psifor 2.5 hours. The catalyst was filtered off and the filtrate extractedwith other. The aqueous phase was concentrated to half volume andapplied to a column (1.5×32 cm) of Dowex 50 resin (Na cycle) that wascooled by a jacket of circulating ice-water. The column was eluted withwater and the fractions monitored by ultraviolet absorption. A broadpeak was obtained in which the front part was more heavily contaminatedwith diphenyl phosphate than the trailing part. The center fraction andthe trailing fraction were isolated separately and the center fractionwas concentrated and immediately rechromatograped on the same column.The trailing fraction from the rechromatography was combined with theoriginal trailing fraction, concentrated and lyophilized to afford theproduct as an amorphous solid (38 mg). The lyophilized center fractionfrom the rechromatography gave additional product (23 mg).

UV(H₂ O) λ max 262(ε 10740), 300(sh, ε 7130, 62% NH₂ OH ext.)nm.

NMR(D₂ O) δ 1.33(d, CH₃ CHOH), 3.11(m, CH₂), 3.30-3.64(m, SCH₂),3.43(dd, H6), 4.16(dt, H5), 4.27(p, CH₃ CHOH), 4.84(HOD), 4.88(m, CH₂N), 7.89(d, thiazolyl H5), 8.10(d, pyridyl H3,H5), 8.85(d, pyridylH2,H6).

EXAMPLE 10

Sodium(1R,5S,6S)-6-[1(R)-hydroxyethyl]-2-[2-[4-[N-(2-thiazolyl)sulfamoylatomethyl]-1-pyridinium]ethylthio]-1-methylcarbapen-2-em-3-carboxylate##STR73##

Procedure and physical data follow.

STEP 1 Sodium(1R,5S,6S)-6-[1(R)-hydroxyethyl]-2-[2-[4-[N-(2-thiazolyl)sulfamoylatomethyl]-1-pyridinium]-ethylthio]-1-methylcarbapen-2-em-3-carboxylate

To a stirred solution of1-(2-mercaptoethyl)-4-[N-(2-thiazolyl)sulfamoylmethyl]pyridiniumhydroxide inner salt (60 mg, 0.16 mmol) in DMF (1 ml) at 0° was addedthe solid 1-methyl bicyclic vinyl phosphate (90 mg, 0.17 mmol) followedby N,N-diisopropylethylamine (0.05 ml, 0.28 mmol). The solution wasstirred at 0° for 30 minutes then diluted with 1:1 tetrahydrofuran-water(7 ml). Sodium bicarbonate (14 mg) and 10% Pd/C (90 mg) were added andthe mixture was shaken under hydrogen at 40 psi for 2 hours. Thecatalyst was filtered off and the filtrate extracted with ether. Theaqueous phase was concentrated and applied to a column (1.5×20 cm) ofDowex 50 resin (Na cycle) that was cooled by a jacket of circulatingice-water. The column was eluted with water and the fractions monitoredby ultraviolet absorption. A single product peak was observed. Thetrailing portion of the peak was concentrated under vacuum andlyophilized to provide the product as an amorphous solid (13 mg).

UV(H₂ O) λ max 265(ε 9420), 300(sh, ε 6390, 49% NH₂ OH ext.)nm.

NMR(D₂ O) δ 1.12(d, 1-CH₃), 1.26(d, CH₃ CHOH), 3.2(m, SCHaHb and H1),3.39(dd, H6), 3.49(td, SCHaHb), 3.98(dd, H5), 4.20(p, CH₃ CHOH),4.77(HOD), 4.79(m, CH₂ N), 7.81(d, thiazolyl H5), 8.00(d, pyridylH3,H5), 8.73(d, pyridyl H2,H6).

EXAMPLE 11 Sodium(1R,5S,6S)-2-[2-(3-carboxylato-1-pyridinium)ethylthio]-6-[1(R)-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate##STR74##

IR (Nujol) 3350(br), 1755, 1645, 1610, 1140 cm⁻¹.

UV (H₂ O) λ max 294 (ε 6890)nm.

UV (H₂ O+NH₂ OH) λ max ext. 294(ε ext. 6070) nm.

NMR (D₂ O) δ 1.12(d, 1-CH₃), 1.27(d, CH₃ CHOH), 3.18-3.4(m, H1),3.42(dd, H6), 3.5-3.7(m, SCH₂), 3.88(dd, H5), 4.24(p, CH₃ CHOH),4.9-5.1(m, CH₂ N), 8.07(t, pyridyl H5), 8.86-8.95(m, pyridyl H4,H6),9.27(s, pyridyl H2).

EXAMPLE 12 Sodium(1R,5S,6S)-2-[2-(3-carboxylatomethyl-1-pyridinium)ethyl-thio]-6-[1(R)-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate##STR75##

UV (H₂) λ max 274(ε 4980), 295(ε 5210) nm.

UV (H₂ O+NH₂ OH) λ max ext. 298(ε ext. 4920) nm.

NMR (D₂ O) δ 1.13(d, 1-CH₃), 1.27(d, CH₃ CHOH), 3.2(m, H1), 3.40(dd,H6), 3.55-3.65(m, SCH₂), 3.79(s, pyridyl CH₂), 391(dd, H5), 4.22(p, CH₃CHOH), 8.00(dd, pyridyl H5), 8.49(d, pyridyl H6), 8.72(d, pyridyl H4),8.79(s, pyridyl H2).

EXAMPLE 13 Sodium(5R,6S)-2-[2-[4-(2-carboxylatoethyl)-1-pyridinum]-ethylthio]-6-[1(R)-hydroxyethyl]carbapen-2-em-3-carboxylate##STR76##

IR (Nujol) 3400(br), 1750, 1640, 1580, 1255, 1130 cm⁻¹.

UV (H₂ O) λ max 223(ε 7650), 252(ε 5120), 294(ε 5200) nm.

UV (H₂ O+NH₂ OH) λ max. ext. 298(ε ext. 4780) nm.

NMR (D₂ O) δ 1.28(d, CH₃ CH), 2.67(t, CH₂ CO₂), 2.92 and 3.07 (two dd,CH₂), 3.20(t, pyridyl CH₂), 3.33 and 3.51(two td, SCH₂), 3.4(m, H6),4.03(dt, H5), 4.21(p, CH₃ CHOH), 4.7-4.9(m, CH₂ N), 7.92(d, pyridylH3,H5), 8.70(d, pyridyl H2,H6).

EXAMPLE 14 Sodium(1R,5S,6S)-2-[2-[4-(2-carboxylatoethyl)-1-pyridiniumethylthio]-6-[1(R)-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate##STR77##

IR (Nujol) 3350(br), 1750, 1640, 1580, 1140 cm⁻¹.

UV (H₂ O) λ max 226(ε 8290), 253(ε 5650), 296(ε 6740) nm.

UV (H₂ O+NH₂ OH) λ max. ext. 298 nm (ε ext. 6280)nm.

NMR (D₂ O) δ 1.12(d, 1-CH₃), 1.28(d, CH₃ CHOH), 2.67(t, CH₂ CO₂),3.20(t, CH₂ CH₂ CO₂), 3.1-3.2(m, H1), 3.27(td, SCHaHb), 3.40(dd, H6),3.52(ddd, SCHaHb), 3.91(dd, H5), 4.23(p, CH₃ CHOH), 4.6-4.8(m, CH₂ N),7.92(d, pyridyl H3,H5), 8.68(d, pyridyl H2,H6).

EXAMPLE 15 Sodium(1R,5S,6S)-2-[2-(3-sulfonato-1-pyridinum)ethylthio]-6-[1(R)-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate##STR78##

IR (Nujol) 3400(br), 1750, 1590, 1555, 11230, 1142, 1050 cm⁻¹.

UV (H₂ O) λ max 270(br, ε 5,500), 293 (ε 6,440)nm.

UV (H₂ O+NH₂ OH) λ max ext. 295 (ε 5,620)nm.

NMR (D₂ O) δ 1.12(d, CH₃ CH), 1.27(d, CH₃ CHOH), 3.17(qd, H1), 3.36 (td,SCHaHb), 3.41(dd, H6), 3.58(ddd, SCHaHb), 3.98(dd, H5), 4.20(p, CH₃CHOH), 4.9-5.1(m, CH₂ N), 8.17(dd, pyridyl H5), 8.92-9.01 (m, pyridylH4,H6), 9.40(s, pyridyl H2).

EXAMPLE 16 Sodium(1R,5S,6S)-2-[2-(4-sulfonato-1-pyridinium)ethylthio]-6-[1(R)-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate##STR79##

IR (Nujol) 3450(br), 1737, 1630, 1590, 1218, 1035 cm⁻¹.

UV (H₂ O) λ max 227(ε 9150), 273(ε 5880), 295(ε 6550)nm.

NMR (D₂ O) δ 1.14(d, 1-CH₃), 1.29(d, CH₃ CHOH), 3.18(qd, H1), 3.30 and3.58(two td, SCH₂), 3.42(dd, H6), 3.98(dd, H5), 4.22(p, CH₃ CHOH),4.9-5.0(m, CH₂ N), 8.39(d, pyridyl H3,H5), 9.05(d, pyridyl H2,H6).

EXAMPLE 17 Sodium(1R,5S,6S)-2-[2-(2-sulfonatomethyl-1-pyridinium)ethylthio]-6-[1(R)-hydroxymethyl]-1-methylcarbapen-2-em-3-carboxylate##STR80##

IR (Nujol) 3425(br), 1740, 1625, 1590, 1235, 1040 cm⁻¹.

UV (H₂ O) λ max 274(ε 9170), 295(ε 7470)nm.

UV (H₂ O+NH₂ OH) λ max ext. 298(ε ext. 6430)nm.

NMR (D₂ O) δ 1.14(d, 1-CH₃), 1.28(d, CH₃ CHOH), 3.18(qd, H1), 3.33(td,SCHaHb), 3.42(dd, H6), 3.57(ddd, SCHaHb), 3.95(dd, H5), 4.22(p, CH₃CHOH), 4.79 and 4.95(d, CH₂ SO₃), 5.0-5.2(m, CH₂ N), 8.03(dt, pyridylH5), 8.17(d, pyridyl H3), 8.60 (t, pyridyl H4), 8.86(d, pyridyl H6).

EXAMPLE 18 Sodium(1R,5S,6S)-2-[2-(3-sulfonatomethyl-1-pyridinium)ethylthio]-6-[1(R)-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate##STR81##

IR (Nujol) 3400(br), 1755, 1715, 1620, 1225, 1145, 1040 cm⁻¹.

UV (H₂ O) λ max 273(ε 5900), 295(ε 6560)nm.

UV (H₂ O+NH₂ OH) λ max ext. 297(ε ext. 5970)nm.

NMR (D₂ O) δ 1.13(d, 1-CH₃), 1.28(d, CH₃ CHOH), 3.15(dq, H1), 3.32(td,SCHaHb), 3.41(dd, H6), 3.55(ddd, SCHaHb), 3.95(dd, H5), 4.22(p, CH₃CHOH), 4.43(s, CH₂ SO₃), 4.8-5.0(m, CH₂ N), 8.09(dd, pyridyl H5),8.66(d, pyridyl H4), 8.86(d, pyridyl H6), 8.95(s, pyridyl H2).

EXAMPLE 19 Sodium(1R,5S,6S)-6-[1(R)-hydroxyethyl]-2-[2-(2-hydroxymethylsulfonatomethyl-1-pyridinium)ethylthio]-1-methylcarbapen-2-em-3-carboxylate##STR82##

UV (H₂ O) λ max 277(ε 10,300) 294(sh, ε 8300) nm.

UV (H₂ O+H₂ OH) λ max ext. 295(ε ext. 5880) nm.

NMR (D₂ O) δ 1.18(d, 1-CH₃), 1.32(d, CH₃ CHOH), 3.21(m, H1), 3.46(dd,H6), 3.3-3.72(m, SCH₂), 3.98(dd, H5), 4.27(p, CH₃ CHOH), 4.45(s, CH₂SO₃), 4.84(HOD), 4.95(t, CH₂ N), 5.21(s, CH₂ OH), 8.28(d, pyridyl H3),8.68(d, pyridyl H4), 8.94(s, pyridyl H6).

EXAMPLE 20 Sodium(1R,5S,6S)-6-[1(R)-hydroxyethyl]-2-[2-[3-(2-sulfonatoethyl)-1-pyridinium]ethylthio]-1-methylcarbapen-2-em-3-carboxylate##STR83##

IR (Nujol) 3410(br), 1745, 1587, 1400, 1180, 1040 cm⁻¹.

UV (0.05M pH 7.0 MOPS buffer) λ max 295 (ε 7720), 272.5(ε 6990), 267.5(ε6920)nm.

UV(buffer+NH₂ OH) λ max ext. 297.5(ε ext. 6920)nm.

NMR(D₂ O) δ 1.14(d, 1-CH₃), 1.28(d, CH₃ CHOH), 3.22(m, H1),3.26-3.54(two m, SCH₂), 3.33 (s, CH₂ CH₂ SO₃), 3.42(dd, H6), 3.95(dd,H5), 4.23(m, CH₃ CHOH), 4.77(HOD), 4.87(m, CH₂ N), 8.02(dd, pyridyl H5),8.56(d, pyridyl H4), 8.72(d, pyridyl H6), 8.83(s, pyridyl H2).

EXAMPLE 21Sodium(1R,5S,6S)-2-[2-[4-(3-sulfonatopropyl)-1-pyridinium]-ethylthio]-6-[1(R)-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate##STR84##

IR (Nujol) 3375 (br), 1742, 1638, 1590, 1175, 1038 cm⁻¹.

UV (H₂ O) λ max 225 (ε 10000), 256(ε 5050), 296(ε 6720)nm.

UV (H₂ O+NH₂ OH) λ max ext. 297 (ε 6360)nm.

NMR (D₂ O) δ 1.12(d, 1-CH₃), 1.28(d, CH₃ CHOH), 2.21(p, CH₂ CH₂ CH₂),3.00(t, pyridyl CH₂), 3.13(t, CH₂ SO₃), 3.17(dq, H1), 3.29(td, SCHaHb),3.39(dd, H6), 3.54(ddd, SCHaHb), 3.89(dd, H5), 4.23 (p, CH₃ CHOH),4.6-4.8(m, CH₂ N), 7.97(d, pyridyl, H3,H5), 8.72(d, pyridyl H2,H6).

EXAMPLE 22 Sodium(5R,6S)-6-[1(R)-hydroxyethyl]-2-[2-[4-[1(R,S)-sulfonatoethyl]-1-pyridinium]ethylthio]carbapen-2-em-3-carboxylate##STR85##

UV (0.05M pH 7.0 MOPS buffer) λ max 295 (ε 6780)nm.

UV (buffer+NH₂ OH) λ max ext 298 (ε ext 5840)nm

NMR (D₂ O) δ 1.30(two d's, CH₃ CH), 1.8(m, CH₃ CHSO₃), 3.03(m, CH₂),3.38(dd, H6), 3.32-3.61(m, SCH₂), 4.05(m, H5), 4.22(m, CH₃ CHOH),4.59(m, CH₃ CHSO₃), 4.82(HOD), 4.87(m, CH₂ N), 8.16(m, pyridyl H3,H5),8.87(d, pyridyl H2, H6).

EXAMPLE 23 Sodium(1R,5S,6S)-6-[1(R)-hydroxyethyl]-2-[2-[4-[1(R,S)-sulfonatoethyl]-1-pyridinium]ethylthio]-1-methylcarbapen-2-em-3-carboxylate##STR86##

IR (Nujol) 3400(br), 1744, 1640, 1590, 1180 1027 cm⁻¹.

UV (0.05M pH 7.0 MOPS buffer) λ max 293 (ε 7870)nm.

UV (buffer+NH₂ OH) λ max ext. 295.5(ε ext. 6730)nm.

NMR (D₂ O) δ 1.10(two d's, CH₃ CH), 1.25(two d's, CH₃ CHOH), 1.76(m, CH₃CHSO₃), 3.14(m, CH₃ CH), 3.21-3.57(m, SCH₂), 3.37(dd, H6), 3.88(m, H5),4.18(m, CH₃ CHOH), 4.54(m, CH₃ CHSO₃), 4.80(HOD), 4.85(m, CH₂ N),8.09(m, pyridyl H3,H5), 8.81(m, pyridyl H2,H6).

EXAMPLE 24 Sodium(5R,6S)-2-[1(R)-hydroxyethyl]-2-[2-(2-methyl-4-sulfonatomethyl-1-pyridinium)ethylthio]carbapen-2-em-3-carboxylate##STR87##

UV (H₂ O) λ max 272(ε 8000), 295(ε 7110, 84% NH₂ OH ext.) nm.

NMR (D₂ O) δ 1.33(d, CH₃ CHOH), 2.97(s, CH₃), 3.03 and 3.15(two dd,CH₂), 3.43(dd, H6), 3.30-3.66(m, SCH₂), 4.13(dt, H5), 4.28(p, CH₃ CHOH),4.51(s, CH₂ SO₃), 4.85 (HOD), 4.89(m, CH₂ N), 7.97(d, pyridyl H5),8.03(s, pyridyl H3), 8.77(d, pyridyl H6).

EXAMPLE 25 Sodium(5R,6S)-6-[1(R)-hydroxyethyl]-2-[2-(3-methyl-4-sulfonatomethyl-1-pyridinium)ethylthio]carbapen-2-em-3-carboxylate##STR88##

UV (H₂ O) λ max 272(ε 7600), 293(ε 7000) nm.

UV (H₂ O+NH₂ OH) λ max ext. 295(ε ext. 5770) nm.

NMR (D₂ O) δ 1.32(d, CH₃ CHOH), 2.66(s, CH₃), 2.95 and 3.09(two dd,CH₂), 3.38(dd, H6), 3.30-3.66(m, SCH₂), 4.09(dt, H5), 4.26(p, CH₃ CHOH),4.59(s, CH₂ SO₃), 4.83(HOD), 8.09(d, pyridyl H5), 8.93(d, pyridyl H6),8.97(s, pyridyl H2).

EXAMPLE 26 Sodium(5R,6S)-2-[2-(3-ethyl-4-sulfonatomethyl-1-pyridinium)ethylthio]-6-[1(R)-hydroxyethyl]carbapen-2-em-3-carboxylate##STR89##

IR (Nujol) 3380(br), 1746, 1635, 1585, 1224, 1035 cm⁻¹.

UV (0.05M pH 7.0 MOPS) λ max 275 (ε 8420), 297 (ε 8060)nm.

UV (buffer+NH₂ OH) λ max ext. 299 (ε ext. 6960) nm.

NMR (D₂ O) δ 1.31(d, CH₃ CH), 1.35(t, CH₃ CH₂), 2.97(m, CH₂), 3.38(dd,H6), 3.4-3.67(m, SCH₂), 4.08(dt, H5), 4.25(p,CH₃ CH), 4.61(s, CH₂ SO₃),4.83(HOD), 4.89(t, CH₂ N), 8.13(d, pyridyl H5), 8.75(d, pyridyl H6),8.78(s, pyridyl H2).

EXAMPLE 27 Sodium(5R,6S)-2-[2-(3-fluoro-4-sulfonatomethyl-1-pyridinium)ethylthio]-6-[1(R)-hydroxyethyl]carbapen-2-em-3-carboxylate##STR90##

UV (H₂ O) λ max 232(ε 13120), 273(ε 9140), 295(ε 8280, 81% NH₂ OH ext.)nm.

NMR (D₂ O) δ 1.34(d, CH₃ CHOH), 3.16(two dd, CH₂), 3.48(dd, H6),3.3-3.7(m, SCH₂), 4.22(dt, H5), 4.3(p, CH₃ CHOH), 4.64(s, CH₂ SO₃), 4.96(m, CH₂ N), 8.3(t, pyridyl H5), 8.86(d, pyridyl H6), 9.16(d, pyridylH2).

EXAMPLE 28 Sodium(1R,5S,6S)-2-[2-(3-fluoro-4-sulfonatomethyl-1-pyridinium)ethylthio]-6-[1(R)-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate##STR91##

UV (H₂ O) λ max 272(ε 7260), 293(ε 6470, 78% NH₂ OH ext.) nm.

NMR (D₂ O) ε 1.26(d, 1-CH₃), 1.39(d, CH₃ CHOH), 3.3-3.7(m, SCH₂ and H1),3.53(dd, H6), 4.18(dd, H5), 4.33(p, CH₃ CHOH), 4.67(s, CH₂ SO₃), 5.0(m,CH₂ N), 8.33(t, pyridyl H5), 8.85(d, pyridyl H6), 9.16(d, pyridyl H2).

EXAMPLE 29 Sodium(1R,5S,6S)-2-[2-(3-chloro-4-sulfonatomethyl-1-pyridinium)ethylthio]-6-[1(R)-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate##STR92##

IR(Nujol) 3400(br), 1745, 1635, 1585, 1040 cm⁻¹.

UV (H₂ O) λ max 241(ε 8170), 285(ε 8590)nm.

UV (H₂ O+NH₂ OH) λ max ext. 295(ε ext. 5830)nm.

NMR (D₂ O) δ 1.15(d, CH₃ CH), 1.28(d, CH₃ CHOH), 3.25(dq, H1), 3.28 and3.57(two td, SCH₂), 3.42(dd, H6), 4.03(dd, H5), 4.23(p, CH₃ CHOH),4.68(s, CH₂ SO₃), 4,7-4.9(m, CH₂ N), 8.22(d, pyridyl H5), 8.81(d,pyridyl H6), 9.14(s, pyridyl H2).

EXAMPLE 30 Sodium(5R,6S)-2-[2-(3-bromo-4-sulfonatomethyl-1-pyridinium)ethylthio]-6-[1(R)-hydroxyethyl]carbapen-2-em-3-carboxylate##STR93##

IR (Nujol) 3400 (br), 1745, 1630, 1585, 1235, 1195, 1038 cm⁻¹.

UV (H₂ O) λ max 243(ε 7,270), 289(ε 9,430)nm.

UV (H₂ O+NH₂ OH) λ max ext. 295(ε ext 6,450)nm.

NMR (D₂ O) δ 1.28(CH₃ CH), 2.98 and 3.11(two dd, CH₂), 3.37(dd, H6),3.36 and 3.55(two td, SCH₂), 4.11(dt, H5), 4.22(p, CH₃ CH), 4.70(s, CH₂SO₃), 4.86-4.88(m, NCH₂), 8.21(d, pyridyl H5), 8.87(dd, pyridyl H6),9.27(d, pyridyl H2).

EXAMPLE 31 Sodium(5R,6S)-2-[2-(3-amino-4-sulfonatomethyl-1-pyridinium)ethylthio]-6-[1(R)-hydroxyethyl]carbapen-2-em-3-carboxylate##STR94##

IR (nujol) 3350(br), 1742, 1640, 1580, 1520, 1225, 1180, 1030 cm⁻¹.

UV (0.05M pH 7.0 MOPS buffer) λ max 257 (ε 7500), 300(ε 8970), 333(ε3990)nm.

UV (buffer+NH₂ OH) λ max ext. 297.5 nm (ε ext 7340).

NMR (D₂ O) δ 1.30(d, CH₃ CH), 2.90 and 3.02(two dd, CH₂), 3,34(dd, H6),3.29-3.56(m, SCH₂), 4.07 (dt, H5), 4.23(p, CH₃ CH), 4.44(s, CH₂ SO₃),4.72(t, CH₂ N), 4.84(HOD), 7.77(d, pyridyl H5), 8.12(d, pyridyl H6),8,25(s, pyridyl H2).

EXAMPLE 32 Sodium(5R,6S)-2-[2-(3-acetamido-4-sulfonatomethyl-1-pyridinium)ethylthio]-6-[1(R)-hydroxyethyl]carbapen-2-em-3-carboxylate##STR95##

IR (nujol) 3380(br), 1745, 1690, 1630, 1585, 1225, 1035 cm⁻¹.

UV (0.05M pH 7.0 MOPS buffer) λ max 250 (ε 8190), 296(ε 9950)nm.

UV (buffer+NH₂ OH) λ max ext 296.5 (ε ext 6300)nm.

NMR (D₂ O) δ 1.29(d, CH₃ CH), 2.35(s, COCH₃), 2.96 and 3.09(two dd's,CH₂), 3.35(dd, H6), 3.4-3.64(m, SCH₂), 4.03(dt, H5), 4.23(p, CH₃ CH),4.64(s, CH₂ SO₃), 4.84(HOD), 4.91(t, CH₂ N), 8.13(d, pyridyl H5),8.72(d, pyridyl H6), 9.38(s, pyridyl H2).

EXAMPLE 33 Sodium(5R,6S)-6-[1(R)-hydroxyethyl]-2-[2-(3-methoxy-4-sulfonatomethyl-1-pyridinium)ethylthio]-carbapen-2-em-3-carboxylate##STR96##

UV (H₂ O) λ max 294(ε 10570, 48% NH₂ OH ext.) nm.

NMR (D₂ O) δ 1.36(d, CH₃ CHOH), 3.08(m, CH₂), 3.44(dd, H6), 3.3-3.7(m,SCH₂), 4.16(s, OCH₃), 4.3(m, H5 and CH₃ CHOH), 4.62(s, CH₂ SO₃), 4.95(t, CH₂ N), 8.14(d, pyridyl H5), 8.62(d, pyridyl H6), 8.66(s, pyridylH2).

EXAMPLE 34 Sodium(5R,6S)-2-[2-(3-methylthio-4-sulfonatomethyl-1-pyridinium)ethylthio]-6-[1(R)-hydroxyethyl]carbapen-2-em-3-carboxylate##STR97##

IR (Nujol) 3400(br) 1740, 1590, 1230, 1190, 1035 cm⁻¹.

UV (H₂ O) λ max 235(ε 10,700), 276(ε 7,480), 298(sh, ε 6,230)nm.

UV (H₂ O+NH₂ OH) δ max est. 299(ε ext. 5,050)nm.

NMR (D₂ O) δ 1.28(d, CH₃ CH), 2.66(s, SCH₃), 2.91 and 3.00 (two dd,CH₂), 3,32(dd, H6), 3.36 and 3.55(two td, SCH₂), 4.06(dt, H5), 4.20(p,CH₃ CH), 4.8-4.9(m, CH₂ N), 8.03(d, pyridyl H5), 8.62(s, pyridyl H2),8.63(d, pyridyl H6).

EXAMPLE 35 Sodium(5R,6S)-6-[1(R)-hydroxyethyl]-2-[2-(3-methoxycarbonyl-4-sulfonatomethyl-1-pyridinium)ethylthio]-carbapen-2-em-3-carboxylate##STR98##

UV (H₂ O) λ max 268(ε 7350), 274(ε 7420), 295(ε 7270, 80% NH₂ OH ext.)nm.

NMR (D₂ O) δ 1.31(d, CH₃ CHOH), 3.00 and 3.12(two dd, CH₂), 3.41(dd,H6), 3.36-3.70(m, SCH₂), 4.09(s, CO₂ CH₃), 4.13(dt, H5), 4.25(p, CH₃CHOH), 4.83(HOD), 4.98(m, CH₂ N), 5.04(s, CH₂ SO₃), 8.27(d, pyridyl H5),9.04(d, pyridyl H6), 9.41 (s, pyridyl H2).

EXAMPLE 36 Sodium(5R,6S)-6-[1(R)-hydroxyethyl]-2-[[5-(3-methoxycarbonyl-4-sulfonatomethyl-1-pyridinium)-3-thia-1-pentyl]thio]carbapen-2-em-3-carboxylate##STR99##

UV (H₂ O) λ max 268(ε 6700), 274(ε 6700), 300(ε 8200, 82% NH₂ OH ext.nm.

NMR (D₂ O) δ 1.35(d, CH₃ CHOH), 2.90-3.36(m, SCH₂ CH₂ SCH₂), 3.10(m,CH₂), 3,47(dd, H6), 4.11(s, CO₂ CH₃), 4.28(m, H5 and CH₃ CHOH),4.83(HOD), 4.95(t, CH₂ N), 5.05(s, CH₂ SO₃), 8.27(d, pyridyl H5),9.04(d, pyridyl H6), 9.41(s, pyridyl H2).

EXAMPLE 37 Sodium(5R,6S)-2-[2-(3-carbamoyl-4-sulfonatomethyl-1-pyridinium)ethylthio]-6-[1(R)-hydroxyethyl]carbapen-2-em-3-carboxylate##STR100##

UV (H₂ O) λ max 268(ε 8000), 274(ε 8070), 295(ε 8500)nm.

UV (H₂ O+NH₂ OH) λ max ext. 300(ε ext. 7100) nm.

NMR (D₂ O) δ 1.32(d, CH₃ CHOH), 3.06 and 3.21(two dd, CH₂), 3.45(dd,H6), 3.38-3.70(m, SCH₂), 4.19(dt, H5), 4.25(p, CH₃ CHOH), 4,81(HOD),4.96(m, CH₂ N), 8.27(d, pyridyl H5), 8.99(d, pyridyl H6), 9.21(s,pyridyl H2).

EXAMPLE 38 Sodium(5R,6S)-2-[2-(3-aminosulfonyl-4-sulfonatomethyl-1-pyridinium)ethylthio]-6-[1(R)-hydroxyethyl]carbapen-2-em-3-carboxylate##STR101##

IR (Nujol) 3400 (br), 1745, 1635, 1585, 1230, 1040 cm⁻¹.

UV (H₂ O) λ max 239 (ε 5,150), 270(ε 4,400), 296(ε 4,350)nm.

UV (H₂ O+NH₂ OH) λ max ext. 297(ε ext. 3,580)nm.

NMR (D₂ O) δ 1.28(d, CH₃ CH), 3.01 and 3.12(two dd, CH₂), 3.3-3.4(m,SCHaHb), 3.40(dd, H6), 3.60(td, SCHaHb), 4.13(dt, H5), 4.22(p, CH₃ CH),4.9-5.0 (m, CH₂ N), 4.9(s, CH₂ SO₃), 8.40(d, pyridyl H5), 9.06(d,pyridyl H6), 9.43(s, pyridyl H2).

EXAMPLE 39 Sodium(5R,6S)-2-[2-[3-(N-methyl)aminosulfonyl-4-sulfonatomethyl-1-pyridinium]ethylthio]-6-[1(R)-hydroxyethyl]carbapen-2-em-3-carboxylate##STR102##

IR (Nujol) 3420 (br), 1745, 1635, 1585, 1228, 1155, 1038 cm⁻¹.

UV(H₂ O) λ max 291 (ε 7,200)nm.

UV (H₂ O+NH₂ OH) λ max ext. 294(ε ext. 6,040)nm.

NMR (D₂ O) δ 1.28(d, CH₃ CH), 2.68(s, NCH₃), 3.01 and 3.12(two dd, CH₂),3.40(dd, H6), 3.41 and 3.59(two td, SCH₂), 4.15(dt, H5), 4.22(p, H8),4.9-5.1(m, CH₂ N), 8.45(d, pyridyl H5), 9.10(d, pyridyl H6), 9.48(s,pyridyl H2).

EXAMPLE 40 Sodium(5R,6S)-6-[1(R)-hydroxyethyl]-2-[3-(4-sulfonatomethyl-1-pyridinium)propylthio]carbapen-2-em-3-carboxylate##STR103##

UV (H₂ O) λ max 254(ε 6,200), 266(ε 6100), 297 (ε 6850)nm.

UV (H₂ O+NH₂ OH) λ max ext. 298(ε 6370) nm.

NMR (D₂ O) δ 1.33(D, CH₃ CHOH), 2.41(m, SCH₂ CH₂ CH₂), 2.78-3.06(m,SCH₂), 3.11 and 3.30(two dd, CH₂), 3.44(dd, H6), 4.25(m, H5 and CH₃CHOH), 4.76(s, CH₂ SO₃), 8.14(d, pyridyl H3,H5), 8.91 (d, pyridylH2,H6).

EXAMPLE 41 Sodium(5R,6S)-6-[1(R)-hydroxyethyl]-2-[2-(4-sulfonatomethyl-1-quinolinium)ethylthio]carbapen-2-em-3-carboxylate##STR104##

UV (H₂ O) λ max 302(ε 8230), 320(ε 6220) nm.

UV (H₂ O+NH₂ OH) λ max ext. 295 (ε ext. 4950) nm.

nmr (D₂ O) δ 1.23(d, CH₃ CHOH), 2.55(m, CH₂), 3.02(dd, H6), 3.49(dt,H5), 3.50-3.80(m, SCH₂), 4.16(p, CH₃ CHOH), 5.11(ABq, CH₂ SO₃), 5.38(m,CH₂ N), 8.12(d, quinolyl H3), 8.19 and 8.37(two dd, quinolyl H6,H7),8.60 and 8.77(two d, quinolyl H5, H8), 9.28(d, quinolyl H2).

EXAMPLE 42 Sodium(1R,5S,6S)-6-[1(R)-hydroxyethyl]-2-[2-(5-sulfonato-2-isoquinolinium)ethylthio]-1-methylcarbapen-2-em-3-carboxylate##STR105##

IR (Nujol) 3400(br), 1740, 1722, 1640, 1583, 1180, 1135, 1110 cm⁻¹.

UV (0.05M pH 7.0 MOPS buffer) λ max 265(ε 3830), 275(ε 3830), 278(ε7110), 286(ε 7180), 293(ε 4810), 339(ε 3350)nm.

UV (buffer+NH₂ OH) λ max ext. 293(ε ext. 4810)nm.

NMR (D₂ O) δ 1.05(d, 1-CH₃), 1.22(d, CH₃ CHOH), 2.98(dq, H1), 3.26(dd,H6), 3.34-3.74(m, SCH₂ and H5), 4.1(p, CH₃ CHOH), 4.84(HOD),4.94-5.28(m, CH₂ N), 8.12(t, isoquinolyl H7), 8.54(d, isoquinolyl H8),8.76(two overlapping d, isoquinolyl H4 and H6), 9.08(d, isoquinolyl H3),9.84(s, isoquinolyl H1).

EXAMPLE 43 Sodium(1R,5S,6S)-6-[1(R)-hydroxyethyl]-2-[2-(3-sulfonatomethyl-1-pyridazinium])ethylthio)-1-methylcarbapen-2-em-3-carboxylate##STR106##

UV (H₂ O) λ max 294(ε 6150, 85% NH₂ OH ext.) nm.

NMR (D₂ O) δ 1.16(d, 1-CH₃), 1.30(d, CH₃ CHOH), 3.32(m, H1), 3.48(dd,H6), 3.35-3.70(m, SCH₂), 4.10(dd, H5), 4.22(p, CH₃ CHOH), 4.70(s, CH₂SO₃), 4.75(HOD), 5.12(t, CH₂ N), 9.08(dd, pyridazinyl H5), 9.18(d,pyridazinyl H4), 9.67(d, pyridazinyl H6).

EXAMPLE 44 Sodium(1R,5S,6S)-6-[1(R)-hydroxyethyl]-2-[2-(4-sulfonatomethyl-1-pyridazinium)ethylthio]-1-methylcarbapen-2-em-3-carboxylate(isomer A) and sodium(1R,5S,6S)-6-[1(R)hydroxy-ethyl]-2-[2-(5-sulfonatomethyl-1-pyridazinium)ethylthio]-1-methylcarbapen-2-em-3-carboxylate(isomer B) ##STR107##

UV (H₂ O) λ max 242(ε 9500), 293(ε 7500, 77% NH₂ OH ext.) nm.

NMR (D₂ O) Isomer A γ 1.21(d, 1-CH₃), 1.32(d, CH₃ CHOH), 3.42(m, H1),3.40-3.78(m, SCH₂), 3.48(dd, H6), 4.18(dd, H5), 4.28(p, CH₃ CHOH),4.64(s, CH₂ SO₃), 4.85(HOD), 5.13(m, CH₂ N), 8.64(dd, pyridazinyl H5),9.60(d, pyridazinyl H3), 9.64(d, pyridazinyl H6).

NMR(D₂ O) Isomer B δ 4.17(dd, H5), 4.57(s, CH₂ SO₃), 8.64(dd,pyridazinyl H4), 9.57 (d, pyridazinyl H3), 9.82(s, pyridazinyl H6).

EXAMPLE 45 Sodium(5R,6S)-6-[1(R)-hydroxyethyl]-2-[2-4-sulfonatomethyl-1-pyrimidinum)ethylthio]carbapen-2-em-3-carboxylate##STR108##

UV (H₂ O) λ max 253(ε 7520), 295(ε 6630, 77% NH₂ OH ext.) nm.

NMR (D₂ O) δ 1.32(d, CH₃ CHOH), 3.12 and 3.28 (two dd, CH₂),3.30-3.70(m, SCH₂), 3.48(dd, H6), 4.26(m, H5 and CH₃ CHOH), 4.44(s, CH₂SO₃), 4.83(HOD), 4.94(m, CH₂ N), 8.37(d, pyrimidyl H5), 9.28(d,pyrimidyl H6), 9.69(s, pyrimidyl H2).

EXAMPLE 46 Sodium(1R,5S,6S)-6-[1(R)-hydroxyethyl]-2-[2-(3-methyl-4-sulfonatomethyl-1-imidazolium)ethylthio]-1-methylcarbapen-2-em-3-carboxylate##STR109##

IR (Nujol) 3430(br), 1740, 1590, 1228, 1043 cm⁻¹.

UV (0.05pH 7.0 MOPS buffer) λ max 297.5 (97% NH₂ OH ext., ε ext. 7240)nm.

NMR (D₂ O) δ 1.15(d, CH₃ CH), 1.29(d, CH₃ CHOH), 3.12 and 3.39( two m's,SCH₂), 3.28(m, H1), 3.43(dd, H6), 3.91(s, NCH₃), 4.08(dd, H5), 4.23(p,CH₃ CHOH), 4.39(s, CH₂ SO₃), 4.47(m, CH₂ N), 4.80(HOD), 7.65(d,imidazolyl H5), 8.79(d, imidazolyl H2).

EXAMPLE 47 Sodium(1R,5S,6S)-6-[1(R)-hydroxyethyl]-2-[2-(3-(2-sulfonatoethyl)-1-imidazolium)ethylthio]-1-methylcarbapen-2-em-3-carboxylate##STR110##

IR (Nujol) 3420(br), 1743, 1580, 1408, 1184, 1043 cm⁻¹.

UV (0.05M pH 7.0 MOPS buffer) λ max 297.5 (97% NH₂ OH ext., ε ext7310)nm.

NMR (D₂ O) δ 1.22(d, CH₃ CH), 1.35(d, CH₃ CHOH), 3.20 and 3.46(two m's,SCH₂), 3.37(m, CH₃ CH), 3.50(dd, H6), 3.51(t, CH₂ SO₃), 4.15(dd, H5),4.31(p, CH₃ CHOH), 4.55 and 4.70(two t's, two CH₂ N), 4.87(HOD), 7.63and 7.71(two t's, imidazolyl H4, H5), 8.98(t, imidazolyl H2),

EXAMPLE 48 Sodium(1R,5S,6S)-6-[1(R)-hydroxyethyl]-2-[2-(2-sulfonatomethyl-3-thiazolium)ethylthio]-1-methylcarbapen-2-em-3-carboxylate##STR111##

UV (H₂ O) λ max 254(ε 8200), 294(ε 7000, 87% NH₂ OH ext.) nm.

NMR (D₂ O) δ 1.17(d, 1-CH₃), 1.30(d, CH₃ CHOH), 3.30(m, H1),3.30-3.62(m, SCH₂), 3.46(dd, H6), 4.06(dd, H5), 4.26(p, CH₃ CHOH),4.82(HOD), 4.93 (t, CH₂ N), 5.06(ADq, CH₂ SO₃), 8.25(d, thiazolyl H5),8.29(d, thiazolyl H4).

EXAMPLE 49 Sodium(1R,5S,6S)-6-[1(R)-hydroxyethyl]-2-[2-(5-sulfonatomethyl-3-thiazolium)ethylthio]-1-methylcarbapen-2-em-3-carboxylate##STR112##

UV (H₂ O) λ max 248(ε 7800), 294(ε 8300), 86% NH₂ OH ext.) nm.

NMR (D₂ O) δ 1.22(d, 1-CH₃), 1.35(d, CH₃ CHOH), 3.30(m, H1),3.30-3.64(m, SCH₂), 3.51(dd, H6), 4.16(dd, H5), 4.31(p, CH₃ CHOH),4.66(s, CH₂ SO₃), 4.85(HOD), 8.47(s, thiazolyl H4).

EXAMPLE 50 Sodium(1R,5S,6S)-6-[1(R)-hydroxymethyl]-2-[2-[4-(N-methyl)-sulfonatoaminomethyl)-1-pyridinium]ethylthio]-1-methylcarbapen-2-em-3-carboxylate##STR113##

IR (Nujol) 3400(br), 1740, 1640, 1590, 1240, 1180, 1035 cm⁻¹.

UV (H₂ O) λ max 220(ε 9730), 257(ε 5750), 296(ε 7420)nm.

UV (H₂ O+NH₂ OH) ε max. ext. 297(ε ext. 6670) nm.

NMR (D₂ O) δ 1.13(d, 1-CH₃), 1.27(d, CH₃ CHOH), 2.77(s, NCH₃), 3.20(qd,H1), 3.29(td, SCHaHb), 3.40(dd, H6), 3.54(ddd, SCHaHb), 3.93(dd, H5),4.21(p, CH₃ CHOH), 4.46(s, pyridyl-CH₂), 4.7-4.9 (m, CH₂ N), 8.07(d,pyridyl H3,H5), 8.77(d, pyridyl H2,H6).

EXAMPLE 51 Sodium(1R,5S,6S)-6-[1(R)-hydroxyethyl]-2-[2-(4-sulfonatomethylamino-1-pyridinium)ethylthio]-1-methylcarbapen-2-em-3-carboxylate##STR114##

IR (Nujol) 3350(br), 1748, 1648, 1590, 1855, 1180, 1035 cm⁻¹.

UV (H₂ O) λ max 213(ε 9420), 283(ε 20000)nm.

UV (H₂ O+NH₂ OH) λ max. ext. 304(ε ext. 7220)nm.

NMR (D₂ O) λ 1.11(d, 1-CH₃), 1.28(d, CH₃ CHOH), 3.10(qd, H1), 3.17(td,SCHaHb), 3.38(dd, H6), 3.41(ddd, SCHaHb), 3.89(dd, H5), 4.22(p, CH₃CHOH), 4.33(ddd, NCHaHb), 4.56(td, NCHaHb), 4.62 and 4.63 (two d, CH₂SO₃), 7.0-7.2(m, pyridyl H3,H5), 8.0-8.2(m, pyridyl H2,H6).

EXAMPLE 52 Sodium(1R,5S,6S)-6-[1(R)-hydroxyethyl]-2-[2-[4-(N-sulfonatocarbamoyl)-1-pyridium]ethylthio]-1-methylcarbapen-2-em-3-carboxylate##STR115##

IR (Nujol) 3400(br), 1748, 1680, 1588, 1040 cm⁻¹.

UV (H₂ O+NH₂ OH) λ max. ext. 295 nm.

NMR (D₂ O) δ 1.18(d, 1-CH₃), 1.31(d, CH₃ CHOH), 3.2-3.42(m, SCHaHb andH1), 3.47(dd, H6), 3.62(dt, SCHaHb), 4.06(dd, H5), 4.26(p, CH₃ CHOH),4.82(HOD), 4.95(m, CH₂ N), 8.39(d, pyridyl H3 and H₅), 9.0(d, pyridyl H2and H6).

EXAMPLE 53

Sodium(1R5S,6S)-2-[2-[4-[(ethoxy)oxidophosphinyl]-1-pyridinium]ethylthio]-6-[1(R)-hydroxyethyl]-1-methyl-carbapen-2-em-3-carboxylate##STR116##

UV (H₂ O) λ max 278, 293(85% NH₂₀ H ext.) nm.

NMR (D₂ O) δ 1.18(d, I-CH₃), 1.3I(d, CH₃ CHOH), 1.42(t, C₂ CH₃),3.18-3.40(m, SCHaHb and H1), 3.46(dd, H6), 3.54-3.74(dt, SCHaHb,4.04(dd, H5), 4.9-5.14(m, CH₂ N), 8.50(dd, pyridyl H3, H5), 9.12(dd,pyridyl H2,H6).

EXAMPLE 54

Sodium(1R5S,6S)-2-[2-[4-[(ethoxy)oxidophosphinyl-methyl]-1pyridinumethylthio]-6-[I(R)-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate##STR117##

UV (H₂ O) λ max 265, 295 (84% NHOH ext.) nm.

NMR (D₂ O) δ 1.9(d, 1-CH₃), 1.36(d, CH₃ CHOH), 1.36(t. CH₃ CH₂),3.1-3.42(m, SCHaHb and H1), 3.49(dd, H6), 3.52-3.72(m, SCHaHb), 4.06(dd,H5), 4.14-4.4(m, CH₃ CHOH and CH₃ CH₂), 4.82(HOD), 4.8-5.0(m, CH₂ N),8.l(dd, pyridyl H3, H5), 8.86(d, pyridyl H2,H6).

EXAMPLE 55

Sodium(1R,5S,6S)-2-[2-[2-[4-[(amino)oxidophosphinylmethyl]-1pyridinium]ethylthio]-6-[1(R)-hydroxyethyl]-1-methylcarbapen-2-em-3carboxylate##STR118##

UV H₂ O) λ max 242( 8520), 292( 5050, 75% NH₂ OH ext.)nm.

NMR (D₂ O) 1.18(d, 1-CH₃), b 1.32(d, CH₃ CHOH), 3.1-3.7(m, SCH₂ and H1),3.43(d, CH₂ P), 3.44(dd, H6), 4.04(dd, H5), 4.28(p, CH₃ CHOH), 7.96(dd,pyridyl H3,H5), 8.70(d, pyridyl H2,H6).

EXAMPLE 56

Sodium(1R,5S,6S)-2-[2-[4-[(hydroxy)oxidophosphinylmethyl]-1pyidinium]ethylthio]-6-[1(R)-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate##STR119##

UV (H₂ O) λ max 248 ( 6480), 292(ε3930) nm.

UV (H₂ O+NH₂ OH) λ max ext. 296(ε ext. 3360) nm.

NMR (D₂ O) 1.17(d, 1-CH₃), 1.31(d, CH₃ CHOH), 3.2-3.7(m, SCH₂ and H1),3.31(d, CH₂ P), 3.44(dd, H6), 4.01(dd, H5), 4.25(p, CH₃ CHOH), 7.91(dd,pyridyl H3,H5), 8.62(d, pyridyl H2,H6).

EXAMPLE 57

Sodium(1R,5S-6S)-2-[-2-[4-[(ethoxy)oxidophosphinyloxymethyl]-1pyridinium]ethylthio]-6-[1(R)-hydroxyethyl]-1-methylcarbapen-2-em-3carboxylate##STR120##

UV (H₂ O) λ max 295 nm.

UV (H₂ O+NH₂ OH) λ max ext 297 (85% ext.) nm.

NMR (D₂ O) δ 1.16(d, I-CH₃), 1.30(d, CH₃ CHOH), 1.40(t, CH₃ CH₂),3.1-3.7(m, SCH₂, H1 and H6), 4.00(dd, H5), 4.8(HOD), 4.7-5.09(m, CH₂ N),5.53(d,pyridyl-CH₂), 8.11(d, pyridyl H3,H5), 8.89(pyridyl H2, H6).

EXAMPLE 58

Potassium (1R5S,6S)-6-[1(R)-hydroxyethyl]-2-[2-[4-(5-tetrazolatomethy-1-pyridinium]ethylthio]-1-methylcarbapen-2-em-1-carboxylate ##STR121##

UV (H₂ O) λ max 256.5, 295 (88% NH₂ OH ext.) nm.

NMR (D₂ O) δ1.06(d, CH₃ CH), 1.28(d, CH₃ CHOH), 3.09(dq, HI),3.15-3.58(m, SCH₂), 3.37(dd, H6), 3.76(dd, H5), 4.20(p, CH₃ CHOH),4.80(m, CH₂ N), 4.84(HOD), 7.87(d, pyridyl H3,H5), 8.71(d, pyridylH2,H6).

EXAMPLE 59

Sodium(1R5S,6S)-2-[2-[4-[1,1-dioxo-3-keto-4-oxido-2,3-dihydro(2H)-1,2,5-thiadiazol-2-ylmethyl]-1-pyridinium]ethylthio]-6-[1(R)-hydroxyethyl]-1-methyl-carbapen-2-em-3-carboxylate##STR122##

IR (Nujol) 3400(br), 1740, 1675, 1640, 1590 1170 cm⁻¹.

UV (H₂ O) λ max 210(ε13600), 258(ε5920), 295(ε6470) nm.

UV (H₂ O+NH₂ OH) λ max ext 297(εext. 5670) nm.

NMR (D₂ O) δ1.12(d, 1-CH₃), 1.29(d, CH₃ CHOH), 3.18(qd, H1), 3.28 and3.53(two td, SCH₂), 3.39(dd, H6), 3.95(dd, H5), 4.24(p, CH₃ CHOH),4.7-4.9 (m, CH₂ N), 5.24(s, pyridiyl CH₂), 8.08(d, pyridyl H3,H5),8.83(d, pyridyl H2,H6).

EXAMPLE 60

Sodium(1R5S,6S)-2-[2-[4-[(N-acetyl)sulfamoylatomethyl]-1-pyridinium]ethylthio]-6-[1(R)-hydroxyethyl]-1-methylcarba-pen-2-em-3-carboxylate##STR123##

UV (H₂ O) λ max 233(ε7990), 292(ε5023, 80% NH₂ OH ext.) nm.

NMR (D₂ O) δ1.17(d, 1-CH₃), 1.32(d,CH₃ CHOH), 3.16-3.41(m, SCHaHb andH1), 3.45(dd, H6), 3.60(td, SCHaHb), 4.04(d, H5), 4.27(p,CH₃ CHOH),4.83(HOD), 4.87(m, CH₂ N), 8.08(d, pyridyl H3,H5), 8.86(d, pyridylH2,H6).

EXAMPLE 61

Sodium (1R5S,6S)-6-[1(R)-hydroxyethyl]-2-[2-[4-(N-methyl-carbamoyl)sulfamoylatomethyl-1-pyridinium]ethylthio]-1-methylcarbapen-2-em-3-carboxylate##STR124##

UV (pH 7 buffer) λ max 292 (ε7400) nm.

UV (buffer+NH₂ OH) λ max ext. 297(εext. 6430)nm.

NMR (D₂ O) δ1.20(d, 1-CH₃), 1.34(d,CH₃ CHOH), 2.74(s, SCH₃), 3.2-3.45(m,SCHaMb and Ml), 3.49(OD H6), 3.64(td, SCHaHb), 4.09(d, H5), 4.29(p, CH₃CHOH), 4.87(HOD), 4.94(m, CH₂ N), 8.14(d, pyridyl H3,H5), 8.92(d,pyridyl H2,H6).

EXAMPLE 62 Sodium(5R,6S)-6-[I(R)-hydroxyethyl]-1-[2-[4-(N-phenyl)sulfamoylmethyl-1-pyridinium]ethylthio]-carbapen-2-em-3-carboxylate##STR125##

UV (H₂ O) λ max 295(ε7380, 66% NH₂ OH ext.) nm. NMR (D₂ O) δ1.32(d,CH₃CHOH), 3.09(m, CH₂), 3.38(m, SCHaHb), 3.42(dd, H6), 3.57(td, SCHaHb),4.15(dt, H5), 4.26(p,CH₃ CHOH), 4.84(HOD masking CH₂ N), 7.15 and7.39(two m, phenyl, 8.05(d, pyridyl H3,H5), 8.82(d, pyridyl H2,H6).

EXAMPLE 63 Sodium(1R5S,6S)-6-[1(R)-hydroxyethyl]-2-[2-[4-(N-methylsulfonyl)carbamoylato-1-pyridinium]ethylthio]-1-methylcarbapen-2-em-3-carboxylate##STR126##

IR (Nujol) 3410(br, 1744, 1597, 1560, 1260, 1145, 1115 cm⁻¹.

UV (0.05M pH 7.0 MOPS buffer) λ max 275(ε10,550), 290(sh, ε 10,310)nm

UV (buffer+NH₂ OH) λ max ext. 295(εext. 6830)nm.

NMR (D₂ O) δ1.21(d, CH₃ CH), 1.35(d,CH₃ CHOH), 3.27(s, SO₂ CH₃), 3.28(m,CH₃ CH), 3.34 and 3.64(two m's SCH₂, 3.49 (dd, H6), 4.04(dd, H5),4.28(p,CH₃ CHOH), 4.87(HOD), 4.98(m, CH₂), 8.50(d, pyridyl H3,H5),9.00(d, pyridyl H2,H6).

EXAMPLE 64 Sodium(1R5S,6S)-6-[1(R)-hydroxyethyl]-2-[2-[4-[N-(p-toluylsulfonyl)carbamoylato]-1-pyridinium)ethylthio)-1-methylcarbapen-2-em-3-carboxylate##STR127##

IR (Nujol) 3380 (br), 1750, 1726, 1638, 1602, 1560, 1263, 1134, 1080cm⁻¹.

UV (0.05 pH 7.0 MOPS buffer) λ max 275(sh, ε11,500), 292(ε 11,830)nm.

UV(buffer+NH20H) λ max ext. 295(εext. 6740)nm.

NMR (D₂ O) δ 1.17(d, CH₃ CH), 1.31(d,CH₃ CHOH), 3.20(m, H1), 3.42(dd,H6), 3.36 and 3.61(two m's, SCH₂), 3.91(dd, H5), 4.12(p,CH₃ CHOH),4.87(HOD), 4.95(t, CH₂ N), 7.48 and 7.91 (two d's, aryl H's), 8.44(d,pyridyI H3,H5), 8.97(d, pyridyl H2,H6).

EXAMPLE 65 Sodium (5R,6S)-6-[I(R)-hydroxyethyl]-2-[2-[4-[(N-cyano)sulfamoylatomethyl]-1-pyridinium]ethylthio]carbapen-2-em-3-carboxylate##STR128##

Detailed procedures and physical data follow:

STEP 1 4-Pyridylmethanesulfonic acid

To a stirred solution of sodium sulfite (500 g, 3.97 mol) in water (1.2l) heated to 60° C. was added a solution of 4-picolyl chloridehydrochloride (300 g, 1.83 mol) in water (300 ml) during a period of 1hr. The resulting solution was heated to 95° C. for an additional hourthen cooled and the excess sodium sulfite decomposed by the slowaddition of conc. HCl (375 ml). The solution was concentrated to a wetcake and ethanol (500 ml) was added. The solid was collected and washedwith additional ethanol (300 ml). The partially dried cake was suspendedin conc. HCl (350 ml) and the NaCl filtered off and washed with moreconc. HCl (100 ml). Ethanol (1.5 l) was slowly added to the combinedfiltrates causing the product to crystallize. After aging at 0° C. for 2hrs, the product was collected, washed with ethanol (200 ml) and driedto give a white solid (235 g, 74% yield). A 200 MHz NMR spectrum of theproduct showed about 6% of the dimeric impurity1-(4-pyridylmethyl)-4-(sulfomethyl)pyridinium chloride.

STEP 2 4-Pyridylmethanesulfonyl chloride triflate

Trifluoromethanesulfonic acid (100 g, 0.67 mol) was rapidly added to asuspension of 4-pyridylmethanesulfonic acid (103 g, 0.6 mol) inphosphorous oxychloride (300 ml). The pyridylmethanesulfonic aciddissolved and reprecipitated as the triflate salt. The resultingsuspension was cooled in ice for 30 min, then treated with phosphorouspentachloride (139 g, 0.67 mol) in Portions during 10 minutes. Themixture was allowed to warm to room temperature over 30 min and was thencautiously heated to reflux over a period of 1.5 hrs during which timeextensive gas evolution occurred. After refluxing for 1 hr, the excessphosphorous oxychloride was distilled off under vacuum while maintainingthe pot temperature below 80° C. The residual solid was dissolved inacetonitrile (200 ml), filtered and crystallized by the gradual additionof ether (400 ml). The product was recovered by filtration and washedwith ether to afford a white solid (170 g, 84%).

mp 116°-118° C.

NMR (CD₃ CN) δ 2.51 (CH₃ CN), 6.05 (s, CH₂ SO₂), 8.79 (d, J=6.3 Hz, H3,H5), 9.39(d, J=6.3 Hz, H2, H6).

STEP 3 N-Cyano-4-pyridylmethanesulfonamide

Anhydrous cyanamide (32 g, 0.76 mol) was dissolved in acetonitrile (600ml) in a 2 l, 3-necked flask equipped with a mechanical stirrer, dryingtube, and two dropping funnels. The solution was cooled in a 1:1ethanol-water bath that was maintained at -20° C. by the addition of dryice. Solutions of pyridine (57 g, 0.72 mol) in acetonitrile (70 ml) andof 4-pyridylmethanesulfonyl chloride triflate (130 g, 0.38 mol) inacetonitrile (200 ml) were added simultaneously at such a rate that theadditions of both solutions were completed in 3 hrs. The resultingsuspension was stirred at -10° C. for 1 hr and then filtered and thesolids washed with cold acetonitrile (50 ml). The solid portion wasrecrystallized by adding it to ice-cold water (100 ml). The product wasfiltered off and washed with ice-water (100 ml) to give a light yellowsolid (49.5 g). The mother liquors were refrigerated overnight to giveadditional product (5 g, 73% total yield).

mp>250° C. (dec).

IR (Nujol) 2165 cm⁻¹.

NMR (D₂ O+NaHCO₃) δ4.28 (s, CH₂ SO₂), 4.71 (HOD), 7.49 (d, J=6.1 Hz, H3,H5), 8.50 (d, J=6.1 Hz, H2, H6).

Microanalytical: Calc'd C, 42.63; H, 3.58; N, 21.31; Found C, 42.63; H,3.68; N, 21.14.

STEP 4 1-[2-(Acetylthio)ethyl]-4-[(N-cyano)sulfamoylmethyl]-pyridiniumhydroxide, inner salt

A solution of N-cyano-4-pyridylmethanesulfonamide (51.7 g, 0.26 mol),2-bromoethyl thiolacetate (95.8 g, 0.52 mol), andN,N-diisopropylethylamine (40.8 g, 0.32 mol) in acetonitrile (500 ml)was heated at 80° C. for 24 hrs. The resulting suspension was filteredand the Precipitate washed with acetonitrile (500 ml) to afford theProduct as a light yellow solid (39.5 g). The filtrate was evaporatedand the residue slurried with methylene chloride (100 ml) to giveadditional product (2.8 g) after filtration. The filtrate wasreevaporated and the residue dissolved in water (200 ml) and applied toa 5×30 cm Dowex 50W-X4 column (sodium form, 200-400 mesh). The columnwas eluted with water (1.2 l) and the eluate was treated with activatedcarbon at room temperature, filtered and evaporated to 100 ml. Theresulting slurry was cooled in ice and the product (7.5 g) recovered byfiltration. The total yield of product was 49.8 g (63.5%).

mp 215° C. (dec).

IR (Nujol) 2165, 1645 cm⁻¹.

NMR (DMSO-d₆) δ 2.31 (s, SCOCH₃), 2.51 (DMSO-d₅ J=6.0 Hz, SCH₂), 4.57(s, CH₂ SO₂), 4.75 (t, J=6.0 Hz, CH₂ N), 8.10 (d, J=6.0 Hz, H3, H5),9.01 (d, J=6.0 Hz, H2, H6).

UV (H₂ O) λ _(max) 260 (ε 6,700), 230 (ε 11,000) nm.

Microanalytical: Calc'd C, 44.13; H, 4.38; N, 14.04; S, 21.42; Found C,43.96; H, 4.40; N, 14.09; S, 21.47.

STEP 5 1-[2-Mercaptoethyl]-4-[(N-cyano)sulfamoylmethyl]-pyridiniumhydroxide, inner salt

The N-acetylthioethyl pyridinium derivative of step 4 (42.7 g, 0.14 mol)was added to a stirred, 10% aqueous ammonium hydroxide solution (450 ml)which had been purged with nitrogen. Immediately after the solutioncleared, it was evaporated under vacuum to an oil. This material wasdiluted with water (500 ml), seeded and reevaporated to 150 ml. Theresulting crystalline slurry was chilled in ice for 30 min, thenfiltered and the cake washed with cold water to afford the product as anoff-white solid (61 g, 94%).

mp 124°-127° C. (eff).

IR (Nujol) 2165 cm⁻¹.

NMR (DMSO-d₆) δ2.51 (DMSO-d₅), 2.71 (t, CH₂ SH), 3.12 (dt, CH₂ SH), 4.58(s, CH₂ SO₂), 4.71 (t, CH₂ N), 8.13 (d, J=6.1 Hz, H3, H5), 9.00 (d,J=6.1 Hz, H2, H6).

STEP 6 p-Nitrobenzyl(5R,6S)-6-[1(R)-hydroxyethyl]-2-[2-[4-[(N-cyano)sulfamoylatomethyl]-1-pyridinium]ethylthio]-carbapen-2-em-3-carboxylate

A suspension of p-nitrobenzyl(5R,6S)-2-(diphenylphosphono)oxy-6-[1(R)-hydroxyethyl]carbapen-2-em-3-carboxylate(75.4 g, 0.13 mol) and the mercaptan of step 5 (30.9 g, 0.12 mol) in DMF(300 ml) was cooled to -15° C. under a nitrogen atmosphere.N,N-Diisopropylethylamine (16.8 g, 0.13 mol) was added via syringe tothe stirred solution during 20 minutes. After an additional 40 min, theDMF was partially evaporated (200 ml) and ethanol (1 l) was slowlyadded. After stirring for 30 min at room temperature, the precipitatewas filtered and washed with ethanol (200 ml). The resulting amorphoussolid was crystallized by adding it in small portions over a period of 1hr to a stirred solution of acetonitrile (600 ml) and water (30 ml)(Note: after 15 g had been added the solution was seeded with 1 g offinely ground Product derived from a previous run). The resultingmixture was stirred for 30 min at room temperature and for 1 hr in anice bath, then filtered and the cake washed with 95% acetonitrile togive the Product as a cream colored powder (63.1 g, 85%). This materialwas found by NMR to be a solvate containing one-half mole ofacetonitrile.

mp 140°-145° C. (dec).

IR (Nujol) 2165, 1775 cm⁻¹.

NMR (DMSO-d₆) δ 1.23 (d, CH₃ CHOH), 2.06 (s, CH₃ CN), 2.49 (DMSO-d₅),3.2-3.6 (m, carbapenem CH₂), 3.40 (dd, H6), 3.54 (t, SCH₂), 3.97 (m, CH₃CHOH), 4.19 (m, H5), 4.57 (s, CH₂ SO₂), 4.83 (t, CH₂ N), 5.13 (d, OH),5.37 (ABq, CH₂ Ar), 7.69 and 8.23 (two d, ArH), 8.13 (d, pyridyl H3,H5), 9.03 (d, pyridyl H2, H6).

STEP 7 Sodium(5R,6S)-6-[1(R)-hydroxyethyl]2-2-2-[4-[(N-cyano)sulfamoylatomethyl]--pyridinium]ethylthiol-carbapen-2-em-3-carboxylate

The ester of step 6 (12.3 g, 0.02 mol) was ground in a mortar with aportion of butanol then transferred to a 2.3 l hydrogenation vesselcontaining the remaining butanol (360 ml total), ethyl acetate (180 ml),water (720 ml), sodium bicarbonate (1.58 g, 0.019 mol), and 10%palladium on carbon (4.5 g). The mixture was hydrogenated at 40 psi for40 min then vented, flushed, repressurized and shaken for an additional80 min. The aqueous layer was filtered through prewashed Solka-Floc toremove catalyst. The organic layer was washed with water (120 ml) andthe aqueous layer used to wash the filter cake. The PH of the combinedaqueous layers was adjusted to 7.0 with dilute HCl. The solution wasevaporated under vacuum to a volume of 150 ml then applied to anice-water jacketed column of SP-207 resin (5×25 cm, 500 ml). The columnwas initially eluted with DI water followed by elution with 5% methanolin water, and the Progress of the separation was followed by UVmeasurement of the absorbance ratio at 295/262nm. The main fraction wascollected when this ratio was greater than 0.92. In a typicalchromatography, a forerun was collected between elution volumes of 700and 1300 ml, the solvent was changed to 5% methanol in water, the mainfraction was collected between 1300 and 3000 ml, and the tails between3000 and 3600 ml. The main fraction was concentrated under vacuum to avolume of 150 ml and freeze-dried to give the product as a light yellowpowder (6.3 g) having a NH₂ OH extinguished UV absorbance at λ _(max)297 nm (ε_(ext) 7000). The combined tails and forerun yielded slightlyless pure product (1.2g) having ε _(ext) 6000. The total isolated yieldbased on an assumed ε _(ext) of 8000 was 68%.

IR (Nujol) 2165, 1745 (br) cm⁻¹.

NMR (D₂ O) δ 1.25 (d, CH₃ CH), 2.92 and 3.07 (two dd, carbapenem CH₂),3.36 H6), 3.34 and 3.52 (two td, SCH₂), 4.06 (dt, H5), 4.19 (dq, CH₃CH), 4.74 (HOD), 4.84 (s, CH₂ SO₂), 4.86 (m, CH₂ N), 8.17 (d, pyridylH3, H5), 8.88 (d, pyridyl H2, H6).

EXAMPLE 66 Sodium(1R,5S,6S)-6-[I(R)-hydroxyethyl]-2-[2-[4-[(N-cyano)sulfamoylatomethyl]-1-pyridinium]ethylthio]-1-methylcarbapen-2-em-3carboxylate##STR129##

Detailed procedures and physical data follow:

STEP 1 1-[2-Mercaptoethyl]-4-[(N-cyano)sulfamoylmethyl]-pyridiniumhydroxide, inner salt

Solid 1-[2-(acetylthio)ethyl]-4-[(N-cyano)-sulfamoylmethyl]pyridiniumhydroxide inner salt (1.5 g, 5.01 mmol) was dissolved in an aqueousammonium hydroxide solution (35 ml) which had been purged with nitrogen.After 1 min, the solution was evaporated under vacuum to remove excessammonia and water. The residue was twice diluted with water andevaporated under vacuum and then diluted with ethanol and pumped dry toafford the crude mercaptan in 100% yield. This material was used in thenext step without further purification.

STEP 2 p-Nitrobenzyl(1R,5S,6S)-6-[1(R)-hydroxyethyl]-2-[2-[4-[(N-cyano)sulfamoylatomethyl]-1-pyridinium]ethylthio]-1-methylcarbapen-2-em-3-carboxylate

The mercaptan from step 1 (5.01 mmol) was dissolved in DMF (15 ml) andthe solution was cooled in an ice bath and stirred under a nitrogenatmosphere. p-Nitrobenzyl(1R,5R,6S)-2-(diphenylphosphono)oxy-6-[1(R)-hydroxyethyl]-1-methyl-carbapen-2-em-3-carboxylate(3.0 g, 5.05 mmol) was added in one portion followed by the dropwiseaddition of N,N-diisopropylethylamine (0.9 ml, 5.17 mmol) over 5 min.The resulting solution was stirred in the cold for 40 min thenevaporated under vacuum to remove the DMF. The syrupy residue wastriturated with ethanol to afford the product (2.88 g, 95%) as anamorphous solid. This material was immediately ester deblocked adescribed in the following step.

STEP 3 Sodium(1R,5S,6S)-6-[1(R)-hydroxyethyl]-2-[2-[4-[(N-cyano)sulfamoylatomethyl]-1-pyridinium]ethylthio]-1-methylcarbapen-2-em-3-carboxylate

The crude ester (2.88 g, 4.79 mmol) from step 2 was dissolved in 1:1THF-H₂ O (300 ml) and treated with NaHCO₃ (0.41 g, 4.88 mmol). Theresulting solution was divided into two equal parts and each portion wastreated with 10% palladium on powdered charcoal (0.75 g) andhydrogenated at 45 psi for 2 hr. The two mixtures were combined andfiltered to remove the catalyst which was washed with water containing afew drops of saturated brine. The aqueous filtrate was extracted withether, acidified from pH 7.35 to pH 6.65 with dilute HCl, and carefullyconcentrated under reduced pressure (foaming) to ca. 20 ml. Thissolution was added to an ice-water jacketed column of SP-207 resin(2.5×32 cm, 160 ml) that was eluted first with DI H₂ O (375 ml), thenwith 5% MeOH/H₂ O (875 ml), and finally with 10% MeOH/H₂ O; 25 mlfractions were collected approximately every 6 min. The progress of theseparation was followed by UV measurement of the absorbance ratio at293/258 nm. Fractions 23-60 (absorbance ratio ≧0.96) were combined,concentrated under vacuum, and freeze-dried to give the product (1.42 g)as a light yellow powder having a NH₂ OH extinguished UV absorbance atλ_(max) 297 nm (ε_(ext) 6800). Fractions 20-22 and fractions 61-75 wereseparately concentrated and freeze-dried to provide slightly less pureproduct. The isolated yield of center cut material was 52% based on anassumed ε_(ext) of 8000 for 100% purity.

NMR (D₂ O)δ1.10 (d, 1-CH₃), 1.23 (d, CH₃ CHOH), 3.20 (m, Hl), 3.26 (td,SCHaHb), 3.40 (dd, H6), 3.53(td, SCHaHb), 3.98(dd, H5), 4.20 (dq, CH₃CHOH), 4.74 (HOD), 4.83 (s, CH₂ SO₂), 4.86 (t, CH₂ N), 8.16 (d, pyridylH3, H5), 8.85 (d, pyridyl H2, H6).

EXAMPLE 67 Sodium (5R,6S)-2-[2-[3-chloro-4-[(N-cyano)sulfamoylatomethyl]-1-pyridinium]ethylthio]-6-[1(R)-hydroxyethyl]carbapen-2-em-3-carboxylate##STR130##

UV (H₂ O+NH₂ OH) λmax ext. 298 (ε ext 4,130)nm.

NMR (D₂ O)δ1.24(d, CH₃ CHOH), 3.04(two dd, CH₂) 3.36(dd, H6), 3.2-3.6(m,SCH₂), 4.09(dt, H5), 4.19(dq, CH₃ CHOH ), 4.75(HOD), 4.86(m, CH₂ N),8.27(d, pyridyl H5), 8.85(d, pyridyl H6), 9.20(s, pyridyl H2).

EXAMPLE 68 Sodium(5R,6S)-2-[2-[3-fluoro-4-[(N-cyano)sulfamoylatomethyl]-1-pyridinium]ethylthio-6-[1(R)-hydroxyethyl]carbapen-2-em-3carboxylate##STR131##

UV (H₂ O) λ max 235(ε7,540), 273(ε7,990), 293(sh, ε6,500)nm.

Uv (H₂ O+NH₂ OH) λ max ext. 297(εext 4,840)nm.

NMR (D₂ O) δ1.27(d, CH₃ CHOH), 3.08(two dd, CH₂), 3.39(dd, H6),3.2-3.6(m, SCH₂), 4.16(dt, H5), 4.2(dq, CH₃ CHOH), 4.89(m, CH₂ N),8.3(t, pyridyl H5), 8.84(d, pyridyl H6), 9.15(d, pyridyl H2).

EXAMPLE 69

Using procedures as described in Examples 1-68, the following formula 1compounds are prepared:

    __________________________________________________________________________     ##STR132##                                                                    Compound No.                                                                          R   L                                                                                       ##STR133##                                             __________________________________________________________________________    1,2     H,CH.sub.3                                                                        CH.sub.2 CH.sub.2                                                                        ##STR134##                                             3       H   CH.sub.2 CH.sub.2                                                                        ##STR135##                                             4       H   CH.sub.2 CH.sub.2                                                                        ##STR136##                                             5,6     H,CH.sub.3                                                                        CH.sub.2 CH.sub.2                                                                        ##STR137##                                             7,8     H,CH.sub.3                                                                        CH.sub.2 CH.sub.2                                                                        ##STR138##                                             9,10    H,CH.sub.3                                                                        CH.sub.2 CH.sub.2                                                                        ##STR139##                                             11,12   H,CH.sub.3                                                                        CH.sub.2 CH.sub.2                                                                        ##STR140##                                             13,14   H,CH.sub.3                                                                        CH.sub.2 CH.sub.2                                                                        ##STR141##                                             15,16   H,CH.sub.3                                                                        CH(CH.sub.3)CH.sub.2                                                                     ##STR142##                                             17,18   H,CH.sub.3                                                                        CH(CH.sub.3)CH.sub.2                                                                     ##STR143##                                             19,20   H,CH.sub.3                                                                        CH.sub.2 CH.sub.2                                                                        ##STR144##                                             21,22   H,CH.sub.3                                                                        CH.sub.2 CH.sub.2                                                                        ##STR145##                                             23,24   H,CH.sub.3                                                                        CH.sub.2 CH.sub.2                                                                        ##STR146##                                             25      H   CH.sub.2 CH.sub.2                                                                        ##STR147##                                             26      H   CH.sub.2 CH.sub.2                                                                        ##STR148##                                             27      H   CH.sub.2 CH.sub.2                                                                        ##STR149##                                             28      H   CH.sub.2 CH.sub.2                                                                        ##STR150##                                             29      H   CH.sub.2 CH.sub.2                                                                        ##STR151##                                             30      CH.sub.3                                                                          CH.sub.2 CH.sub.2                                                                        ##STR152##                                             31      CH.sub.3                                                                          CH.sub.2 CH.sub.2                                                                        ##STR153##                                             32      CH.sub.3                                                                          CH.sub.2 CH.sub.2                                                                        ##STR154##                                             33,34   H,CH.sub.3                                                                        CH.sub.2 CH.sub.2                                                                        ##STR155##                                             35      CH.sub.3                                                                          CH.sub.2 CH.sub.2                                                                        ##STR156##                                             36      CH.sub.3                                                                          CH.sub.2 CH.sub.2                                                                        ##STR157##                                             37      CH.sub.3                                                                          CH.sub.2 CH.sub.2                                                                        ##STR158##                                             38      CH.sub.3                                                                          CH.sub.2 CH.sub.2                                                                        ##STR159##                                             39      CH.sub.3                                                                          CH.sub.2 CH.sub.2                                                                        ##STR160##                                             40      CH.sub.3                                                                          CH.sub.2 CH.sub.2                                                                        ##STR161##                                             41      CH.sub.3                                                                          CH.sub.2 CH.sub.2                                                                        ##STR162##                                             42      CH.sub.3                                                                          CH.sub.2 CH.sub.2                                                                        ##STR163##                                             43      CH.sub.3                                                                          CH.sub.2 CH.sub.2                                                                        ##STR164##                                             44,45   H,CH.sub.3                                                                        CH.sub.2 CH.sub.2                                                                        ##STR165##                                             46,47   H,CH.sub.3                                                                        CH.sub.2 CH.sub.2                                                                        ##STR166##                                             48      H   CH.sub.2 CH.sub.2                                                                        ##STR167##                                             49      CH.sub.3                                                                          CH.sub.2 CH.sub.2                                                                        ##STR168##                                             50,51   H,CH.sub.3                                                                        CH.sub.2 CH.sub.2                                                                        ##STR169##                                             52,53   H,CH.sub.3                                                                        CH(CH.sub.3)CH.sub.2                                                                     ##STR170##                                             54,55   H,CH.sub.3                                                                        CH(CH.sub.3)CH.sub.2                                                                     ##STR171##                                             56,57   H,CH.sub.3                                                                        CH(CH.sub.3)CH.sub.2                                                                     ##STR172##                                             58,59   H,CH.sub.3                                                                        CH(CH.sub.3)CH.sub.2                                                                     ##STR173##                                             60,61   H,CH.sub.3                                                                        CH(CH.sub.3)CH.sub.2                                                                     ##STR174##                                             62,63   H,CH.sub.3                                                                        CH(CH.sub.3)CH.sub.2                                                                     ##STR175##                                             62,63   H,CH.sub.3                                                                        CH(CH.sub.3)CH.sub.2                                                                     ##STR176##                                             64,65   H,CH.sub.3                                                                        CH.sub.2                                                                                 ##STR177##                                             66,67   H,CH.sub.3                                                                        CH.sub.2 CH.sub.2                                                                        ##STR178##                                             68,69   H,CH.sub.3                                                                        CH.sub.2 CH.sub.2                                                                        ##STR179##                                             70,71   H,CH.sub.3                                                                        CH.sub.2 CH.sub.2                                                                        ##STR180##                                             72      H   CH.sub.2 CH.sub.2                                                                        ##STR181##                                             73      H   CH.sub.2 CH.sub.2                                                                        ##STR182##                                             74      H   CH.sub.2 CH.sub.2                                                                        ##STR183##                                             75      H   CH.sub.2 CH.sub.2                                                                        ##STR184##                                             76,77   H,CH.sub.3                                                                        CH(CH.sub.3)CH.sub.2                                                                     ##STR185##                                             78,79   H,CH.sub.3                                                                        CH.sub.2 CH.sub.2                                                                        ##STR186##                                             80      H   CH.sub.2 CH.sub.2                                                                        ##STR187##                                             81      H   CH.sub.2 CH.sub.2                                                                        ##STR188##                                             82,83   H,CH.sub.3                                                                        CH.sub.2 CH.sub.2                                                                        ##STR189##                                             84,85   H,CH.sub.3                                                                        CH.sub.2 CH.sub.2                                                                        ##STR190##                                             86,87   H,CH.sub.3                                                                        CH.sub.2 CH.sub.2                                                                        ##STR191##                                             88,89   H,CH.sub.3                                                                        CH.sub.2 CH.sub.2                                                                        ##STR192##                                             90,91   H,CH.sub.3                                                                        CH.sub.2 CH.sub.2                                                                        ##STR193##                                             92,93   H,CH.sub.3                                                                        CH.sub.2 CH.sub.2                                                                        ##STR194##                                             94,95   H,CH.sub.3                                                                        CH.sub.2 CH.sub.2                                                                        ##STR195##                                             96,97   H,CH.sub.3                                                                        CH.sub.2 CH.sub.2                                                                        ##STR196##                                             98,99   H,CH.sub.3                                                                        CH.sub.2 CH.sub.2                                                                        ##STR197##                                             100,101 H,CH.sub.3                                                                        CH.sub.2 CH.sub.2                                                                        ##STR198##                                             102,103 H,CH.sub.3                                                                        CH.sub.2 CH.sub.2                                                                        ##STR199##                                             104,105 H,CH.sub.3                                                                        CH.sub.2 CH.sub.2                                                                        ##STR200##                                             106,107 H,CH.sub.3                                                                        CH.sub.2 CH.sub.2                                                                        ##STR201##                                             108,109 H,CH.sub.3                                                                        CH.sub.2 CH.sub.2                                                                        ##STR202##                                             110     CH.sub.3                                                                          CH.sub.2 CH.sub.2                                                                        ##STR203##                                             111     H   CH.sub.2 CH.sub.2                                                                        ##STR204##                                             112     H   CH.sub.2 CH.sub.2                                                                        ##STR205##                                             113     H   CH.sub.2 CH.sub.2                                                                        ##STR206##                                             114     H   CH.sub.2 CH.sub.2                                                                        ##STR207##                                             115     H   CH.sub.2 CH.sub.2                                                                        ##STR208##                                             116,117 H,CH.sub.3                                                                        CH.sub.2 CH.sub.2                                                                        ##STR209##                                             118,119 H,CH.sub.3                                                                        CH.sub.2 CH.sub.2                                                                        ##STR210##                                             120     H   CH.sub.2 CH.sub.2                                                                        ##STR211##                                             121,122 H,CH.sub.3                                                                        CH.sub.2 CH.sub.2                                                                        ##STR212##                                             123     H   CH.sub.2 CH.sub.2                                                                        ##STR213##                                             124,125 H,CH.sub.3                                                                        CH.sub.2 CH.sub.2                                                                        ##STR214##                                             126,127 H,CH.sub.3                                                                        CH.sub.2 CH.sub.2                                                                        ##STR215##                                             128,129 H,CH.sub.3                                                                        CH.sub.2 CH.sub.2                                                                        ##STR216##                                             130,131 H,CH.sub.3                                                                        CH.sub.2 CH.sub.2                                                                        ##STR217##                                             132     CH.sub.3                                                                          CH.sub.2 CH.sub.2                                                                        ##STR218##                                             133     CH.sub.3                                                                          CH.sub.2 CH.sub.2                                                                        ##STR219##                                             __________________________________________________________________________

What is claimed is:
 1. A compound of the formula: ##STR220## wherein: Ris H or CH₃ ;R¹ is CH₃ CH(OH)--; R² is H; ##STR221## is a quaternary,monocyclic, substituted heteroary group comprising pyridinium, which isrequired to be substituted in the 4-position by an acidic sidechain ofthe structure -B, where B is optionally attached by way of a bridginggroup which is a member selected from the group consisting essentiallyof --CH₂ --; and B is an acidic function which is a member selected fromthe group consisting essentially of sulfo (SO₃ H); SO₂ NHCN; andheteroarylsulfonamino (SO₂ NHR^(x)), where R^(x) is substituted orunsubstituted heteroaryl, selected from thiazole and thiadiazole; andwhere the heteroaryl group is substituted, it is mono- or disubstitutedby a member or members independently selected from the group consistingessentially of C₁ -C₄ alkyl; CF₃ ; carbamoyl, and cyano; the heteroarylgroup ##STR222## is optionally substituted by one to three of theradicals independently selected from the group consisting of:(a) atrifluoromethyl group; --CF₃ ; (b) a halogen atom: --Br, --Cl --F, or--I; (c) C₁ -C₄ alkoxy radical; --OC₁₋₄ alkyl; (d) a hydroxy group:--OH; (e) an amino group, or a mono (C₁ C₄ alkyl) amino or di(C₁ -C₄alkyl) amino group: ##STR223## where R^(y) and R^(z) are independently Hor C₁ -C₄ alkyl; (f) C₁ -C₆ alkyl radical; and L is --CH₂ CH₂ --; and Yis is selected from;(i) COOH or a pharmaceutically acceptable thereof;(ii) COOM wherein M is an alkali metal or other pharmaceuticallyacceptable salt; and (iii) COOM where M is a negative charge in the casewhere a permanent positive charge exists elsewhere in the molecule.
 2. Acompound according to claim 1 wherein the ##STR224## group with theacidic sidechain and optional substituent is selected from the groupconsisted of: ##STR225##
 3. A compound according to claim 1 wherein theacidic sidechain B is SO₃ H, CH₂ SO₃ H, or CH₂ SO₂ NHCN, while theoptional substituent thereon is selected from the group consisting of:Cl and F.
 4. The compounds ##STR226## wherein R =H, CH₃ ; R'=H, F, Cl;and R"=0 or NCN.
 5. A compound selected from the group consisting of

    ______________________________________                                         ##STR227##                                                                    Compound No.                                                                             R                                                                                    ##STR228##                                                 ______________________________________                                        1          H                                                                                     ##STR229##                                                 2          H                                                                                     ##STR230##                                                 5          H                                                                                     ##STR231##                                                 6          H                                                                                     ##STR232##                                                 7          H                                                                                     ##STR233##                                                 8          H                                                                                     ##STR234##                                                 9          H                                                                                     ##STR235##                                                 10         H                                                                                     ##STR236##                                                 11         H                                                                                     ##STR237##                                                 14         H                                                                                     ##STR238##                                                 15         H                                                                                     ##STR239##                                                 16         CH.sub.3                                                                              ##STR240##                                                 17         CH.sub.3                                                                              ##STR241##                                                 19         CH.sub.3                                                                              ##STR242##                                                 20         CH.sub.3                                                                              ##STR243##                                                 21         CH.sub.3                                                                              ##STR244##                                                 22         CH.sub.3                                                                              ##STR245##                                                 24         H                                                                                     ##STR246##                                                 25         H                                                                                     ##STR247##                                                 26         H                                                                                     ##STR248##                                                 27         CH.sub.3                                                                              ##STR249##                                                 28         CH.sub.3                                                                              ##STR250##                                                 29         CH.sub.3                                                                              ##STR251##                                                 ______________________________________                                    


6. A pharmaceutical composition for antibacterial use comprising anantibacterially effective amount of a compound of claim 1 and apharmaceutically acceptable carrier thereof.
 7. A method of treatingbacterial infections in human or animal subjects in need of suchtreatment comprising adminstering to such subject an antibacteriallyeffective amount of a compound of claim
 1. 8. The combination of acompound of claim 1 and a DHP inhibitor.
 9. The combination of acompound of claim 4 and the DHP inhibitor7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptanoicacid.
 10. A pharmaceutical composition for antibacterial use comprisingan antibacterially effective amount of a compound of claim 1 aninhibitorily effective amount of a DHF inhibitor, and a pharmaceuticallyacceptable carrier thereof.
 11. A pharmaceutical composition accordingto claim 10 wherein the DHP inhibitor is7-(L-2-amino-2-carboxyethylthio)-2(2,2-dimethylcyclopropanecarboxyamide)-2-heptanoic acid.
 12. A method oftreating bacterial infections in human or animal subjects in need ofsuch treatment comprising coadminstering to such subject anantibacterially effective amount of a compound of claim 1 and aninhibitorily effective amount of a DHP inhibitor.
 13. A method accordingto claim 12 wherein the DHP inhibitor is7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptanoicacid.